Pyrazole-amides and -sulfonamides

ABSTRACT

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides pyrazole-amides and -sulfonamides, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain by blocking sodium channels associated with the onset or recurrance of the indicated conditions. The compounds, compositions and methods of the present invention are of particular use for treating neuropathic or inflammatory pain by the inhibition of ion flux through a channel that includes a PN3 subunit.

CROSS-REFERENCES TO RELATED APPLICATIONS

This is a non-provisional filing of U.S. Provisional Patent Application No. 60/335,958, filed on Nov. 1, 2001, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

This invention relates to the use of certain pyrazole amide and pyrazole sulfonamide compounds as sodium channel inhibitors and to the treatment of neuropathic pain by the inhibition of sodium channels. Additionally, this invention relates to novel pyrazole-based compounds that are useful as sodium channel inhibitors.

BACKGROUND OF THE INVENTION

Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states, and have found particular use as local anesthetics and in the treatment of cardiac arrhythmias. It has also been reported that sodium channel-blocking agents may also be useful in the treatment of pain, including neuropathic pain; see, for example, Tanelian et al. Pain Forum. 4(2), 75-80 (1995). Preclinical evidence demonstrates that sodium channel-blocking agents selectively suppress abnormal ectopic neural firing in injured peripheral and central neurons, and it is via this mechanism that they are believed to be useful for relieving pain. Consistent with this hypothesis, it has been shown that sodium channels accumulate in the peripheral nerve at sites of axonal injury (Devor et al. J. Neurosci. 132: 1976 (1993)). Alterations in either the level of expression or distribution of sodium channels within an injured nerve, therefore, have a major influence on the pathophysiology of pain associated with this type of trauma.

An increasing body of evidence suggests that a voltage-dependent, tetrodotoxin (TTX)-resistant Na channel, PN3 (Na_(v)1.8), may play a key role in sensitization in neuropathic pain states. Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperalgesia.

PN3 is a member of a family of voltage-gated sodium channel alpha subunits. Names for this family include SCN, SCNA, and Na_(v)x.x. There are currently 10 known members falling into two subfamilies Na_(v)1 (all but SCN6A) and Na_(v)2 (SCN6A). The human channel was cloned by Rabert et al. (Pain 78(2): 107-114 (1998)). PN3 of other species has also been cloned. See, for example, Chen et al., Gene 202(1-2), 7-14 (1997); Souslova et al., Genomics 41(2), 201-209 (1997); Akopian et al., Nature 379(6562), 257-262 (1996).

PN3-null mutant mice exhibit a pronounced analgesia to mechanical noxious stimuli (Akopian A. N. et al., Nature Neurosci., 2(6): 541-548 (1999)). Selective “knock down” of PN3 protein in the rat dorsal root ganglion with specific antisense oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either chronic nerve or tissue injury (Porreca et al., Proc. Nat. Acad. Sci., USA, 96: 7640-7644 (1999)). The biophysical properties of PN3 make it ideally suited to sustain repetitive firing of sensory neurons at the depolarized potentials characteristic of injured peripheral nerves. In both human and animal models of neuropathic pain, there is an increased expression of PN3 at the site of peripheral nerve injury (Clare et al., DDT 5: 506-519 (2000); Coward et al., Pain 85: 41-50 (2000)).

Patients with neuropathic pain do not respond to non-steroidal anti-inflammatory drugs (NSAIDS) and resistance or insensitivity to opiates is common. Most other treatments have limited efficacy or undesirable side effects. Mannion et al., Lancet, 353: 1959-1964 (1999) from the Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School wrote: “There is no treatment to prevent the development of neuropathic pain, nor to adequately, predictably and specifically control established neuropathic pain.”

PN3 is a promising molecular target for the treatment of neuropathic pain. One of the most attractive features of PN3 is the highly restricted and peripheral nature of its expression. Antisense studies have revealed no overt (particularly CNS-related) adverse effects, consistent with the localized, peripheral distribution of the channel (Novakovic et al., J. Neurosci., 18(6): 2174-2187 (1998)). Additionally, the high activation threshold of PN3 suggests that the channel may be relatively uninvolved in normal nociception. These properties of PN3 present the possibility that selective blockade of this particular voltage-gated sodium channel (VGSC) may offer effective pain relief without the significant side effect liability normally associated with more promiscuous VGSC blocking drugs. The compounds of the invention are potent inhibitors of PN3 channels.

Ohkawa et al. have described a class of cyclic ethers that are of use as sodium channel blockers (U.S. Pat. No. 6,172,085).

Currently, gabapentin is the market leading treatment for neuropathic pain. As with epilepsy, its mechanism of action for pain is unknown. It is a very safe, easy to use drug, which contributes to its sales. Efficacy for neuropathic pain is not impressive, as few as only 30% of patients respond to gabapentin treatment. Carbamazepine is also used to treat neuropathic pain.

In view of the limited number of agents presently available and the low levels of efficacy of the available agents, there is a pressing need for compounds that are potent, specific inhibitors of ion channels implicated in neuropathic pain. The present invention provides such compounds, methods of using them, and compositions that include the compounds.

SUMMARY OF THE INVENTION

It has now been discovered that pyrazole-amides and -sulfonamides are potent inhibitors of sodium channels. In the discussion that follows, the invention is exemplified by reference to the inhibition of sodium channels that are localized in the peripheral nervous system, and in particular those inhibitors that are selective inhibitors of PN3, and are useful for treating neuropathic pain through the inhibition of sodium ion flux through channels that include the PN3 subunit. The focus of the discussion is for clarity of illustration only.

The compounds and methods of the present invention are useful for treating diseases in which blocking or inhibiting one or more PN3 ion channel provides relief from the disease. Of particular interest is the use of the compounds and methods of the invention for treating pain and central or peripheral nervous system disorders. The present invention is of use for treating both inflammatory and neuropathic pain.

The present invention provides compounds which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides compounds, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain.

In one aspect, the present invention provides compounds according to Formula I:

or a pharmaceutically acceptable salt thereof. In Formula I, the symbols R¹ and R³ are independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl, (C₁-C₆)heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl. The symbol R² represents hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, or heteroaryl(C₁-C₄)alkyl;

The symbol Y is a member selected from:

wherein X is a member selected from O, S and NR⁸. The symbol R⁸ represents hydrogen, cyano, nitro, alkyl, acyl, aryl or SO₂R⁹. R⁹ is selected from alkyl, aryl, heteroaryl and heterocycloalkyl. The symbols R⁴ and R⁵ independently represent hydrogen, (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₃-C₈)heterocycloalkyl, with the proviso that if R⁴ is hydrogen, R⁵ is not hydrogen. R⁴ and R⁵ taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring. The symbol R⁶ represents hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl or (C₁-C₆)heteroalkyl. R⁷ is selected from (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkenyl, (C₁-C₆)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino, alkoxy, (C₃-C₈)heterocycloalkyl and amino(C₁-C₅)alkyl, and and R⁶ and R⁷ together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.

In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound provided above.

In yet another aspect, the present invention provides a method for inhibiting ion flux through voltage dependent sodium channels, comprising contacting a cell containing the target ion channels with a compound that comprises a pyrazolyl moiety, such as the compounds of Formula I.

In still another aspect, the present invention provides a method for the treatment of diseases through inhibition of ion flux through voltage dependent sodium channels, the method comprising treating the host with an effective amount of a sodium channel inhibiting compound comprising a pyrazolyl moiety, such as a compound of Formula I.

Other objects, advantages and embodiments of the invention will be apparent from review of the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a table displaying structures of representative compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS Definitions

The term “pain” refers to all categories of pain, including pain that is described in terms of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and neuropathic pain (abnormal response of a injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g., mild, moderate, or severe; and pain that is a symptom or a result of a disease state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic neuropathy (see, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al., J. of Medicinal Chem. 42:1481-1485 (1999), herein each incorporated by reference in their entirety).

“Somatic” pain, as described above, refers to a normal nerve response to a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer, and includes both cutaneous pain (e.g., skin, muscle or joint derived) and visceral pain (e.g., organ derived).

“Neuropathic” pain, as described above, refers to pain resulting from injury to or chronic changes in peripheral and/or central sensory pathways, where the pain often occurs or persists without an obvious noxious input.

“Biological medium,” as used herein refers to both in vitro and in vivo biological milieus. Exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.

“Compound of the invention,” as used herein refers to the compounds discussed herein, pharmaceutically acceptable salts and prodrugs of these compounds.

“Inhibiting” and “blocking,” are used interchangeably herein to refer to the partial or full blockade of a PN3 channel by a compound of the invention, which leads to a decrease in ion flux either into or out of a cell in which a PN3 channel is found.

Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents which would result from writing the structure from right to left, e.g., —CH₂O— is intended to also recite —OCH₂—; —NHS(O)₂— is also intended to represent. —S(O)₂HN—, etc.

The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.” Alkyl groups, which are limited to hydrocarbon groups are termed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by —CH₂CH₂CH₂CH₂—, and further includes those groups described below as “heteroalkylene.” Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

The term “amino” refers to —NRR′ in which R and R′ are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl.

The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the term “heteroalkylene” by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

In general, an “acyl” or “acyl substituent” is also selected from the group set forth above. As used herein, the term “acyl substituent” refers to groups attached to, and fulfilling the valence of a carbonyl carbon that is either directly or indirectly attached to the nucleus of the compounds of the present invention.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, 1-pyrrolidine, 2-pyrrolidine, 3-pyrrolidine and the like.

The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C₁-C₄)alkyl” is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazole, 3-pyrazolyl, 4-pyrazole, 5-pyrazole, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 2-benzthiazole, 2-benzoxazole, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and “heteroaryl”) include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl, and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generally referred to as “alkyl substituents” and “heteroalkyl substituents,” respectively, and they can be one or more of a variety of groups selected from, but not limited to: -hydrogen, —OR′, ═O, ═NR″″, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR′C(O)R″, —NR′″—C(O)NR′R″, —NR′C(O)₂R″, —NR′″—C(NR′R″)═NR″″, —NR′″—C(NR′R″)═NR″″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′SO₂R″, —NR′″SO₂NR′R″—CN, —R′ and —NO₂ in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R′, R″, R′″ each preferably independently refer to hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, (e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups), substituted or unsubstituted heteroaryl and substituted or unsubstituted arylalkyl. R″″ refers to hydrogen, alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, —CN, —NO₂ and —S(O)₂R′. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical, the aryl substituents and heteroaryl substituents are generally referred to as “aryl substituents” and “heteroaryl substituents,” respectively and are varied and selected from, for example: hydrogen, —OR′, —C═NR″″NR′R″, —NR′″SO₂NR′R″, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″—C(O)NR′R″, —NR″C(O)₂R′, —NR′″—C(NR′R″)═NR″″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN and —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″ and R′″ each preferably independently refer to hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, (e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups), substituted or unsubstituted heteroaryl and substituted or unsubstituted arylalkyl. R″″ refers to hydrogen, alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, —CN, —NO₂ and —S(O)₂R′. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″ and R″″ groups when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl and 4-morpholinyl.

Two of the aryl substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)—(CRR′)_(q)-U-, wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH₂)_(r)-B-, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferably independently selected from hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

The symbol “R” is a general abbreviation that represents a substituent group that is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl groups.

The symbol

, whether utilized as a bond or displayed perpendicular to a bond indicates the point at which the displayed moiety is attached to the remainder of the molecule, solid support, etc.

The term “pharmaceutically acceptable salts” includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Description of the Embodiments

I. Inhibitors of Voltage-Dependent Sodium Channels

In one aspect, the present invention provides compounds having the formula:

or a pharmaceutically acceptable salt thereof. In Formula I, the symbols R¹ and R³ independently represent hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl, (C₁-C₆)heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl. R² is a moiety selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl.

The symbol Y represents a member selected from:

wherein X is selected from O, S and NR⁸. The symbol R⁸ represents hydrogen, cyano, nitro, alkyl, acyl, aryl or SO₂R⁹. R⁹ is selected from alkyl, aryl, heteroaryl and heterocycloalkyl.

R⁴ and R⁵ are independently selected from hydrogen, (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₃-C₈)heterocycloalkyl, with the proviso that if R⁴ is hydrogen, R⁵ is not hydrogen. R⁴ and R⁵ taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.

The symbol R⁶ represents hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl or (C₁-C₆)heteroalkyl; and R⁷ is selected from (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkenyl, (C₁-C₆)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino, alkoxy, (C₃-C₈)heterocycloalkyl and amino(C₁-C₅)alkyl. R⁶ and R⁷ together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.

In a presently preferred embodiment Y is a member selected from:

in which R⁴, R⁵, R⁶, R⁷, and X are as described above.

In another exemplary embodiment, the invention provides a compound having a structure according to Formula II:

in which R¹, R², R³, and Y are as described above. In this embodiment, R¹ and R³ are preferably each independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl and (C₁-C₅)heteroalkyl. R² is preferably selected from aryl and heteroaryl; and X is preferably O.

In a further exemplary embodiment, R⁴ and R⁵ taken together with the nitrogen to which they are attached form a ring system such as that set forth below:

In another preferred embodiment, R³ is hydrogen; R⁴ is selected from (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl and heteroaryl(C₁-C₄)alkyl; and R⁵ is selected from hydrogen or alkyl. Alternatively, R⁴ and R⁵ taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring.

In yet a further preferred embodiment, the invention provides a compound in which R⁴ is a member selected from:

wherein n is an integer from 0 to 4; and k is an integer from 1 to 3. The symbols R^(2a) and R^(2b) are independently selected from hydrogen and (C₁-C₄)alkyl, and R^(2a) and R^(2b) taken together with the carbon atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocycloalkyl ring.

The symbol M represents a moiety that is selected from NR¹⁰, O and S, wherein R¹⁰ is selected from hydrogen, (C₁-C₆) alkyl, (C₁-C₈) heteroalkyl aryl, heteroaryl and (C₃-C₈) cycloalkyl. A, B, D, E and G are independently moieties selected from N,N-oxide and CR¹¹, with the proviso that at most three of A, B, D, E and G is N; and at most one of A, B, D, E and G is N-oxide.

R¹¹ is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)heteroalkyl, aryl, heteroaryl, (C₃-C₈)heterocycloalkyl, alkoxy, acyl, —C(NR¹²)R¹³, —SO₂R¹⁵, —SO₂NR¹³R¹⁴, —NR¹²SOR¹⁵, —NR¹²SO₂NR¹³R¹⁴, —NR¹²C(N—CN)NR¹³R¹⁴, —NR¹²C(N—SO₂R¹⁵)NR¹³R¹⁴, —NR¹²C(N—COR¹⁵)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹²(C═CH—NO₂)NR¹³R¹⁴, —NR¹²CONR¹³R¹⁴, —NR¹²CO—OR¹⁵, —OCONR¹³R¹⁴, and R¹¹ and R^(2a) taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl group with the proviso that A is CR¹¹.

R^(11a) is selected from (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₈)heterocycloalkyl, aryl and heteroaryl. The symbols R¹², R¹³ and R¹⁴ independently represent hydrogen, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl, (C₃-C₈)heterocycloalkyl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino(C₁-C₄)alkyl and when R¹³ and R¹⁴ are attached to the same nitrogen atom, they are optionally combined to form a 5-, 6- or 7-membered ring.

R¹⁵ is selected from (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl and (C₃-C₈)heterocycloalkyl

When R⁴ has a cyclic structure set forth above, R¹ and R³ are preferably each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl and (C₁-C₅)heteroalkyl; and X is O. R² is a preferably a member selected from aryl or heteroaryl.

In yet another preferred embodiment, the invention provides a compound in which R⁴ has a structure according to Formula III:

In Formula III, W is preferably selected from S, SO or SO₂ or a single bond. SO₂ is presently most preferred. The symbol R¹⁵ represents a moiety selected from (C₁-C₄)alkyl, (C₁-C₆)alkenyl, (C₃-C₇)cycloalkyl, aryl, heteroaryl, (C₁-C₈)heteroalkyl, NR¹⁶R¹⁷. R¹⁶ and R¹⁷ are independently selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, (C₃-C₈)heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino(C₁-C₄)alkyl, with the proviso that when R¹⁵ is amino W is SO₂;

The symbols T¹, T², T³ and T⁴ are each independently selected from hydrogen, halo, amino, cyano, nitro, (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₄)haloalkyl, alkoxy, fluoro(C₁-C₄)alkoxy, (C₁-C₇)cycloalkyl, (C₁-C₇)heteroalkyl, aryl and heteroaryl. T¹ and T² taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring. T² and T³ taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring. T³ and R¹⁵ taken together with the atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring. T⁴ and R¹⁵ taken together with the atoms to which they are attached optionally form a 4-to 8-membered carbocyclic or heterocycloalkyl ring.

In a preferred embodiment, R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl or (C₁-C₅)heteroalkyl; and X is O. R² is preferably a member selected from aryl or heteroaryl.

Representative compounds of the invention are set forth in Example 24 and FIG. 1. Activities towards PN3 of selected compounds of the invention are provided in Table 1. The compound numbers in Table 1 are cross-referenced to the compound numbers set forth in the Example and figures. TABLE 1 Activity in Flux Compound # Assay 20 +++ 23 ++ 39 +++ 114 + 154 +++ 323 +++ 411 +++ 414 +++ 444 ++ 449 +++ 480 +++ 1054 +++ 1175 ++ (+++ 0.1-4 μM; ++ 4.1-10 μM; + 10.1-30 μM)

Also within the scope of the present invention are compounds of the invention that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of the invention or reactive analogues thereof. The poly- and multi-valent species can be assembled from a single species or more than one species of the invention. For example, a dimeric construct can be “homodimeric” or “heterodimeric.” Moreover, poly- and multi-valent constructs in which a compound of the invention or a reactive analogue thereof, is attached to an oligomeric or polymeric framework (e.g., polylysine, dextran, hydroxyethyl starch and the like) are within the scope of the present invention. The framework is preferably polyfunctional (i.e. having an array of reactive sites for attaching compounds of the invention). Moreover, the framework can be derivatized with a single species of the invention or more than one species of the invention.

Moreover, the present invention includes compounds within the motif set forth in Formula I, which are functionalized to afford compounds having water-solubility that is enhanced relative to analogous compounds that are not similarly functionalized. Thus, any of the substituents set forth herein can be replaced with analogous radicals that have enhanced water solubility. For example, it is within the scope of the invention to, for example, replace a hydroxyl group with a diol, or an amine with a quaternary amine, hydroxy amine or similar more water-soluble moiety. In a preferred embodiment, additional water solubility is imparted by substitution at a site not essential for the ion channel activity of the compounds set forth herein with a moiety that enhances the water solubility of the parent compounds. Methods of enhancing the water-solubility of organic compounds are known in the art. Such methods include, but are not limited to, functionalizing an organic nucleus with a permanently charged moiety, e.g., quaternary ammonium, or a group that is charged at a physiologically relevant pH, e.g. carboxylic acid, amine. Other methods include, appending to the organic nucleus hydroxyl- or amine-containing groups, e.g. alcohols, polyols, polyethers, and the like. Representative examples include, but are not limited to, polylysine, polyethyleneimine, poly(ethyleneglycol) and poly(propyleneglycol). Suitable functionalization chemistries and strategies for these compounds are known in the art. See, for example, Dunn, R. L., et al., Eds. POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS, ACS Symposium Series Vol. 469, American Chemical Society, Washington, D.C. 1991.

Preparation of Sodium Channel Inhibitors

Compounds of the present invention may be prepared using starting materials readily available from commercial suppliers or known intermediates. Examples of starting materials available from commercial suppliers include, but are not limited to, 3-methyl-2-phenylpyrazole-4-carboxylic acid, 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid, 1-4-chlorophenyl)-5-propyl-1H-pyrazole-4-carboxylic acid, 2-(4-chlorophenyl)-3-trifluoromethyl)pyrazole-4-carboxylic acid, 1-4-(4-chlorophenyl)-1,3-thiazole-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid, 5-fluoro-1-phenylpyrazole-4-carboxylic acid and 1-(4-fluorophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid. Scheme 1 sets forth an exemplary synthetic scheme for the preparation of known intermediates used to prepare compounds of the invention.

In Scheme 1, anhydride a is contacted with allyl ether b to form adduct c. The pyrazole ring system d is formed by contacting adduct c with hydrazine or a hydrazine derivative. The trifluoromethyl group of the pyrazole ketone d is removed by treatment with base to afford the carboxylic acid e.

Numerous routes are available for elaborating the carboxylic acid moiety of intermediates of the invention. In an exemplary procedure, the pyrazole carboxylic acid (compound f; Scheme 2) is activated via conversion to the carboxylic acid chloride (compound g; Scheme 2) and made to react with an amine (e.g.; HNR⁴R⁵) in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of a base such as triethylamine or pyridine to give an amide of Formula I where Y is:

and X is O (compound h; Scheme 2). One skilled in the art will recognize that an amide of the invention may be converted to a thioamido (i.e.; X is S) by treatment with Lawesson's reagent or other methods known in the literature.

Compounds of the present invention may also be prepared as shown in Schemes 3-6. In Scheme 3, the pyrazole amine (compound i) is made to react with a carboxylic acid chloride (e.g.; R⁷COCl) using similar conditions described above to give the amide of formula I where Y is

R⁶ is H and Z is O.

In Scheme 4, the pyrazole amine (i) may be made to react with an isocyanate in an organic solvent such as dichloromethane or tetrahydrofuran to give the urea (compound k) where Y is

R⁶ is H, Z is O and R⁷ is amino. Alternatively, the pyrazole amine (compound i) may be made to react with an isothiocyanate to give a thiourea (i.e.; Z is S).

In Scheme 5, the pyrazole amine (i) may be made to react with the oxazolidinone intermediate (compound l) in an organic solvent such as tetrahydrofuran, acetonitrile or n-butanol, typically at elevated temperature (50-100° C.), to give the sulfenyl urea. Methods used to prepare oxazolidinone are described in the literature.

In Scheme 6, the pyrazole amine may be made to react with the phenoxy intermediate in an organic solvent such as tetrahydrofuran, acetonitrile or n-butanol, typically at elevated temperature (50-100° C.), to give the cyanoguanidine. Methods used to prepare the phenoxy intermediate are described in the literature.

II. Assays for Blockers of Sodium Ion Channels

PN3 monomers as well as PN3 alleles and polymorphic variants are subunits of sodium channels. The activity of a sodium channel comprising PN3 subunits can be assessed using a variety of in vitro and in vivo assays, e.g., measuring current, measuring membrane potential, measuring ion flux, e.g., sodium or guanidinium, measuring sodium concentration, measuring second messengers and transcription levels, and using e.g., voltage-sensitive dyes, radioactive tracers, and patch-clamp electrophysiology.

A number of experimental models in the rat are appropriate for assessing the efficacy of the compounds of the invention. For example, the tight ligation of spinal nerves described by Kim et al., Pain 50: 355-363 (1992) can be used to experimentally determine the effect of the compounds of the invention on a PN3 channel. For example, a sodium channel blockade in vitro assay can be used to determine the effectiveness of compounds of Formula I as sodium channel blockers in an in vitro model by the inhibition of compound action potential propagation in isolated nerve preparations (Kourtney and Stricharz, LOCAL ANESTHETICS, Springer-Verlag, New York, 1987). The mechanical allodynia in vivo assay is also of use in determining the efficacy of compounds of the invention (Kim and Chung Pain 50:355 (1992)). Mechanical sensitivity can be assessed using a procedure described by Chaplan et al., J. Neurosci. Methods 53: 55-63 (1994). Other assays of use are known to those of skill in the art. See, for example, Loughhead et al., U.S. Pat. No. 6,262,078.

Inhibitors of the PN3 sodium channels can be tested using biologically active recombinant PN3, or naturally occurring TTX-resistant sodium channels, or by using native cells, like cells from the nervous system expressing a PN3 channel. PN3 channels can be isolated, co-expressed or expressed in a cell, or expressed in a membrane derived from a cell. In such assays, PN3 is expressed alone to form a homomeric sodium channel or is co-expressed with a second subunit (e.g., another PN3 family member) so as to form a heteromeric sodium channel. Exemplary expression vectors include, but are not limited to, PN3-pCDNA3.1. The PN3 channel is stably expressed in mammalian expression systems.

Inhibition can be tested using one of the in vitro or in vivo assays described above. Samples or assays that are treated with a potential sodium channel inhibitor or activator are compared to control samples without the test compound, to examine the extent of inhibition. Control samples (untreated with activators or inhibitors) are assigned a relative sodium channel activity value of 100. Inhibition of channels comprising PN3 is achieved when the sodium channel activity value relative to the control is less than 70%, preferably less than 40% and still more preferably, less than 30%. Compounds that decrease the flux of ions will cause a detectable decrease in the ion current density by decreasing the probability of a channel comprising PN3 being open, by decreasing conductance through the channel, decreasing the number of channels, or decreasing the expression of channels.

Changes in ion flux may be assessed by determining changes in polarization (i.e., electrical potential) of the cell or membrane expressing the sodium channel. A preferred means to determine changes in cellular polarization is by measuring changes in current or voltage with the voltage-clamp and patch-clamp techniques, using the “cell-attached” mode, the “inside-out” mode, the “outside-out” mode, the “perforated cell” mode, the “one or two electrode” mode, or the “whole cell” mode (see, e.g., Ackerman et al., New Engl. J. Med. 336: 1575-1595 (1997)). Whole cell currents are conveniently determined using the standard methodology (see, e.g., Hamil et al., Pflugers. Archiv. 391: 85 (1981). Other known assays include: radiolabeled rubidium flux assays and fluorescence assays using voltage-sensitive dyes (see, e.g., Vestergarrd-Bogind et al., J. Membrane Biol. 88: 67-75 (1988); Daniel et al., J. Pharmacol. Meth. 25: 185-193 (1991); Holevinsky et al., J. Membrane Biology 137: 59-70 (1994)). Assays for compounds capable of inhibiting or increasing sodium flux through the channel proteins can be performed by application of the compounds to a bath solution in contact with and comprising cells having a channel of the present invention (see, e.g., Blatz et al., Nature 323: 718-720 (1986); Park, J. Physiol. 481: 555-570 (1994)). Generally, the compounds to be tested are present in the range from about 1 pM to about 100 mM, preferably from about 1 pM to about 1 μM.

The effects of the test compounds upon the function of the channels can be measured by changes in the electrical currents or ionic flux or by the consequences of changes in currents and flux. Changes in electrical current or ionic flux are measured by either increases or decreases in flux of ions such as sodium or guanidinium ions (see, e.g., Berger et al., U.S. Pat. No. 5,688,830). The cations can be measured in a variety of standard ways. They can be measured directly by concentration changes of the ions or indirectly by membrane potential or by radio-labeling of the ions. Consequences of the test compound on ion flux can be quite varied. Accordingly, any suitable physiological change can be used to assess the influence of a test compound on the channels of this invention. The effects of a test compound can be measured by a toxin-binding assay. When the functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as transmitter release, hormone release, transcriptional changes to both known and uncharacterized genetic markers, changes in cell metabolism such as cell growth or pH changes, and changes in intracellular second messengers such as Ca²⁺, or cyclic nucleotides.

High throughput screening (HTS) is of use in identifying promising candidates of the invention. Physiologically, Na channels open and close on a ms timescale. To overcome the short time in which channels are open the HTS assay can be run in the presence of an agent that modifies the gating of the channel, such as deltamethrin. This agent modifies the gating of Na channels and keeps the pore open for extended periods of time. In addition, while Na channels are primarily selective for Na, other monovalent cations can permeate the channel.

The specificity and effect of the PN3 blocking agents of the invention can also be assayed against non-specific blockers of PN3, such as tetracaine, mexilitine, and flecainide.

III. Pharmaceutical Compositions of Sodium Channel Openers

In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a pyrazole, such as a compound according to Formula I.

Formulation of the Compounds (Compositions)

The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a neutral compound of the invention or a pharmaceutically acceptable salt thereof.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

IV. Methods for Inhibiting Ion Flow in Voltage-Dependent Sodium Channels

In yet another aspect, the present invention provides methods for decreasing ion flow through voltage dependent sodium channels in a cell, comprising contacting a cell containing the target ion channels with a sodium channel-inhibiting amount of a pyrazole, such as a compound of Formula I.

The methods provided in this aspect of the invention are useful for the diagnosis of conditions that can be treated by inhibiting ion flux through voltage-dependent sodium channels, or for determining if a patient will be responsive to therapeutic agents, which act by inhibiting sodium channels.

V. Methods for Treating Conditions Mediated by Voltage-Dependent Sodium Channels

In still another aspect, the present invention provides a method for the treatment of a disorder or condition through inhibition of a voltage-dependent sodium channel. In this method, a subject in need of such treatment is administered an effective amount of a pyrazole compound, such as a compound according to Formula I. In a preferred embodiment, the compounds provided herein are used to treat a disorder or condition by inhibiting an ion channel of the voltage gated sodium channel family, e.g., PN3.

The compounds provided herein are useful as sodium channel inhibitors and find therapeutic utility via inhibition of voltage-dependent sodium channels in the treatment of diseases or conditions. The sodium channels that are typically inhibited are described herein as voltage-dependent sodium channels such as the PN3 sodium channels.

The compounds of the invention are particularly preferred for use in the treating, preventing or ameliorating pain or seizures. The method includes administering to a patient in need of such treatment, a therapeutically effective amount of a pyrazole compound, e.g., a compound of the invention or a pharmaceutically acceptable salt thereof.

The compounds, compositions and methods of the present invention are of particular use in treating pain, including both inflammatory and neuropathic pain. Exemplary forms of pain treated by a compound of the invention include, postoperative pain, osteoarthritis pain, pain associated with metastatic cancer, neuropathy secondary to metastatic inflammation, trigeminal neuralgia, glossopharangyl neuralgia, adiposis dolorosa, burn pain, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain, pain following stroke, thalamic lesions, radiculopathy, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.

Idiopathic pain is pain of unknown origin, for example, phantom limb pain. Neuropathic pain is generally caused by injury or infection of the peripheral sensory nerves. It includes, but is not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies.

Moreover, any sodium channel inhbitory substance possessed of satisfactory sodium channel inhibiting activity coupled with favorable intracranial transfer kinetics and metabolic stability is expected to show good efficacy in central nervous system (CNS) diseases and disorders such as central nervous system ischemia, central nervous system trauma (e.g. brain trauma, spinal cord injury, whiplash injury, etc.), epilepsy, seizures, neurodegenerative diseases (e.g. amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neuropathy, etc.), vascular dementia (e.g. multi-infarct dementia, Binswanger's disease, etc.), manic-depressive psychosis, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine, ataxia, bipolar disorder, spasticity, mood disorders, psychotic disorders, hearing and vision loss, age-related memory loss, learning deficiencies, anxiety and cerebral edema.

In treatment of the above conditions, the compounds utilized in the method of the invention are administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily. A daily dose range of about 0.1 mg/kg to about 100 mg/kg is more typical. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

EXAMPLES

The following examples are offered to illustrate, but not to limit the claimed invention.

In the examples below, unless otherwise stated, temperatures are given in degrees Celsius (° C.); operations were carried out at room or ambient temperature (typically a range of from about 18-25° C.; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (typically, 4.5-30 mmHg) with a bath temperature of up to 60° C.; the course of reactions was typically followed by thin layer chromatography and reaction times are provided for illustration only; products exhibited satisfactory ¹H-NMR and/or LCMS data; yields (when provided) are for illustration only; and the following conventional abbreviations are also used: mp (melting point), L (liter), mL (milliliters), mmol (millimoles), g (grams), mg (milligrams), min (minutes), LCMS (liquid chromatography-mass spectrometry) and h (hours), PS (polystyrene), DIEA (diisopropylethylamine).

Example 1 Preparation of 1-(3-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

1,1,1,5,5,5-Hexafluoro-3-isobutoxymethylen-pentane-2,4-dione was prepared according to experimental procedures described in Synthesis 1990, 347-350.

3-Chlorophenylhydrazine (1.04 g, 7.29 mmol) was added to a solution of 1,1,1,5,5,5-hexafluoro-3-isobutoxymethylen-pentane-2,4-dione (2.13 g, 7.29 mmol) in acetonitrile (3 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 16 h and concentrated under reduced pressure. The crude residue was treated with methanol (25 mL) and potassium hydroxide (2.00 g) and the reaction mixture refluxed for 18 h. The reaction mixture was concentrated under reduced pressure and the crude product was taken up in water, acidified with 6M hydrochloric acid and extracted with ethyl acetate (5×50 mL). The organic layers were collected, concentrated and crude product purified by column chromatography on silica gel to give 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid. LCMS m/z=288.9(M−H)⁻.

Example 2 Preparation of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid-pyridine-4-ylamide

1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.324 mmol) was added to a solution of 4-aminopyridine (0.036 g, 0.387 mmol) and pyridine (0.078 mL, 0.969 mmol) in acetonitrile (10 mL). The reaction mixture was heated at 60° C. for 12 h, concentrated and the crude product was purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid pyridine-4-ylamide. LCMS m/z=366.9 (M+H)⁺.

Example 3 Preparation of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methane sulfonyl-phenyl)-amide

1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.250 g, 0.808 mmol) was added to a solution of 3-methylsulfonylaniline hydrochloride (0.184 g, 0.889 mmol) and triethylamine (0.563 mL, 4.04 mmol) in acetonitrile (20 mL). The reaction mixture heated at 60° C. for 12 h, concentrated and crude product purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methane sulfonyl-phenyl)-amide. ¹H-NMR (CD₃OD, 300 MHz) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.97 (d, 1H, J=8.5 Hz), 7.73 (d, 1H, J=8.0 Hz), 7.59-7.66 (m, 3H), 7.51 (d, 2H, J=8.8 Hz), 3.15 (s, 3H); LCMS m/z=443.9 (M+H)⁺.

Example 4 Preparation of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide

1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.324 mmol) was added to a solution of 2-(3-fluoro-phenyl)ethylamine (0.051 mL, 0.389 mmol) and triethylamine (0.135 mL, 0.972 mmol) in acetonitrile (10 mL). The reaction mixture stirred for 1 hr at room temperature, concentrated and crude product purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide. LCMS m/z=412.0 (M+H)⁺.

Example 5 Preparation of 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide)

Benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.083 g; 0.189 mmol) was added to a solution of 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.050 g; 0.172 mmol), 3-trifluoromethyl benzylamine (0.030 g; 0.206 mmol) and triethylamine (0.072 mL; 0.516 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 4 h, concentrated and the crude product purified by column chromatography on silica gel to give 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide. LCMS m/z=448.8 (M+H)⁺.

Example 6 Preparation of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2,4-difluoro-phenyl)-amide)

2-4-difluoro-phenylamine (0.004 g; 0.029 mmL) was added to a suspension of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.010 g; 0.032 mmol) and PS-DIEA (0.1 g) in acetonitrile (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time PS-trisamine (0.1 g) was added to remove the excess acid chloride. After an additional 12 h of shaking, the reaction mixture was filtered and concentrated to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2,4-difluoro-phenyl)-amide. LCMS m/z=399.8 (M−H)⁻.

Example 7 Preparation of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2-fluoro-3-trifluoromethyl-phenyl)-amide

2-Fluoro-3-trifluoromethyl-phenylamine (0.007 g; 0.039 mmol) was added to a suspension of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.010 g; 0.032 mmol) and PS-DIEA (0.1 g) in acetonitrile (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time PS-TSCl (0.2 g) high loading was added to remove the excess amine. After an additional 12 h of shaking, the reaction mixture was filtered and concentrated to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2-fluoro-3-trifluoromethyl-phenyl)-amide. LCMS m/z=449.9 (M−H)⁻.

Example 8 Preparation of 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide

3-Trifluoromethyl benzylamine (0.014 mL, 0.100 mmole) was added to a suspension of 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.030 g; 0.109 mmol) and PS-Carbodiimide (0.2 g) in methylene chloride (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time the reaction mixture was filtered and concentrated to give 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide. LCMS m/z=432.3 (M+H)⁺.

Example 9 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-ylamine

Bromine (4.70 mL, 100 mmol) was added to a solution of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid amide (1.20 g, 4.15 mmol) in 3M NaOH (100 mL). The reaction mixture was heated at 100° C. for 1 hour, cooled to room temperature and extracted with EtOAc (3×50 mL). Organic layers were collected, concentrated and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-ylamine (0.408 g, 38%).

Example 10 Preparation of 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-3-(3-methanesulfonyl-phenyl)-urea

Triphosgene (0.042 g, 0.140 mmol) was added to a solution of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-ylamine (0.100 g, 0.382 mmol) and Na₂CO₃ (0.405 g, 3.82 mmol) in CH₂Cl₂/H₂O (50 mL, 1:1) and stirred at room temperature for 30 min. 3-Methanesulfonyl-phenylamine HCl (0.095 g, 0.458 mmol) was added to the reaction mixture, stirred at room temperature for 2 hrs, organic layer collected and aqueous layer extracted with EtOAc (3×25 mL). Organic layers were collected, concentrated and crude product purified by column chromatography to give 1-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-3-(3-methanesulfonyl-phenyl)-urea (0.040 g, 22%).

Example 11

Excess 3,4-dichlorophenylisocyanate was added to a solution of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-ylamine (13.1 mg, 0.05 mmol) in THF (1 mL). The reaction was shaken overnight then the excess 3,4-dichlorophenylisocyanate was scavenged with PS-trisamine. The product (21.4 mg, 95%) was isolated by filtration and evaporation.

Example 12 Preparation of 3-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzenesulfonyl fluoride

1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (3.00 g, 9.70 mmol) was added to 3-amino-benzenesulfonyl fluoride (1.87 g, 10.6 mmol) in CH₂Cl₂ (50 ml) containing pyridine (2.35 ml, 29.1 mmol). Reaction mixture stirred overnight at room temperature, concentrated under reduced pressure and crude product purified by column chromatography to give 3-{[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzenesulfonyl fluoride (3.23 g, 74%).

Example 13 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-cyclopropylsulfamoyl-phenyl)-amide

Cyclopropyl amine (0.012 mL, 0.167 mmol) was added to 3-{[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzenesulfonyl fluoride (0.025 g, 0.055 mmol) in CH₂Cl₂ (10 ml). Reaction mixture stirred overnight at room temperature, concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-cyclopropylsulfamoyl-phenyl)-amide (0.015 g, 55%).

Example 14 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-cyano-2-phenyl-isourea)-amide

Diphenyl N-cyanocarbonimidate (0.235 g, 0.984 mmol) was added to 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-amino-phenyl)-amide (0.250 g, 0.656 mmol) in CH₃CN (10 mL) and heated at 80° C. overnight. Reaction mixture concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-cyano-2-phenyl-isourea)-amide (0.258 g, 75%).

Example 15 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid N′-methyl-cyanoguanidine

1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-cyano-2-phenyl-isourea)-amide (0.050 g, 0.095 mmol) was added to a solution of methyl amine (10 mL, 20 mmol, 2M in THF) and stirred overnight. Reaction mixture concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid N′-methyl-cyanoguanidine (0.038 g, 88%).

Example 16 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methylsulfone-2-phenyl-isourea)-amide

Diphenyl N-methylsulfone-carbonimidate (0.573 g, 1.97 mmol) was added to 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-amino-phenyl)-amide (0.500 g, 1.31 mmol) in CH₃CN (20 mL) and heated at 80° C. for 2 days. Reaction mixture concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methylsulfone-2-phenyl-isourea)-amide (0.700 g, 92%).

Example 17 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(N′-methylsulfone-N″-cyclopropyl-guanidino)-phenyl]-amide

1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methylsulfone-2-phenyl-isourea)-amide (0.025 g, 0.0432 mmol) was added to a solution of cyclopropyl amine (0.030 mL, 0.432 mmol) in THF (5 mL) and stirred overnight. Reaction mixture concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(N′-methylsulfone-N″-cyclopropyl-guanidino)-phenyl]-amide (0.015 g, 65%).

Example 18 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-boronic acid-phenyl)-amide

1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.323 mmol) was added to 3-amino-boronic acid monohydrate (0.060 g, 0.388 mmol) in CH₂Cl₂ (5 ml) containing pyridine (0.078 ml, 0.970 mmol). Reaction mixture stirred 2 hours at 80° C., concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-boronic acid-phenyl)-amide. (0.130 g, 98%).

Example 19 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-thiazol-2-yl-phenyl)-amide

Dichlorobis(triphenylphosphine)palladium (II) (0.002 g, 0.00244 mmol) was added to a degassed (N₂) mixture of 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-boronic acid-phenyl)-amide (0.100 g, 0.244 mmol), Na₂CO₃ (0.052 g, 0.488 mmol), and 2-Bromo-thiazole (0.048 g, 0.292 mmol) in H₂O/toluene (1 mL/2 mL). Reaction mixture heated at 80° C. for 12 hours, cooled to room temperature and extracted with EtOAc (3×5 mL). Organic layers were collected, concentrated and crude product purified by column chromatography to give 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-thiazol-2-yl-phenyl)-amide (0.074 g, 67%).

Example 20 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-sulfamide-phenyl)-amide

Sulfamide (0.010 g, 0.105 mmol) was added to 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-amino-phenyl)-amide (0.020 g, 0.00525 mmol) in 1,4-dioxane (2 mL) and heated at 120° C. overnight. Reaction mixture concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-sulfamide-phenyl)-amide (0.013 g, 54%).

Example 21 Preparation of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-dimethylsulfamide-phenyl)-amide

Dimethylsulfamoyl chloride (0.010 g, 0.105 mmol) was added to 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-amino-phenyl)-amide (0.025 g, 0.0656 mmol) in CH₃CN (2 mL) containing pyridine (0.016 mL, 0.196 mmol). Reaction mixture stirred overnight, concentrated under reduced pressure and crude product purified by column chromatography to give 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-dimethylsulfamide-phenyl)-amide (0.019 g, 59%).

Example 22 ¹⁴C Guanidinium Ion Influx Binding Assay

PN3 stably expressed in a host cell line were maintained in DMEM with 5% fetal bovine serum and 300 μg/ml G-418. The cells were subcultured and grown to confluence in 96-well plates 24-48 h before each experiment. After the growth medium was removed, the cells were washed with warm buffer (25 mM Hepes-Tris, 135 mM choline chloride, 5.4 mM potassium chloride, 0.98 mM magnesium sulfate, 5.5 mM glucose, and 1 mg/ml BSA, pH 7.4) and incubated in buffer on a 36° C. slide warmer for approximately 10 minutes. Various concentrations of the test compounds or standard sodium channel blockers (10 μM) and then deltamethrine (10 μM) were added to each well. After the cells were exposed to deltamethrine for 5 minutes, 5 μM of ¹⁴C-guanidinium was added, incubated with the radioligand (30-60 min), washed with ice-cold buffer, and dissolved in 0.1N sodium hydroxide. The radioactivity and the protein concentration of each cell lysate were determined by liquid scintillation counting and the protein assay using Pierce BCA reagent.

Example 23 23.1 Mechanical Allodynia In vivo Assay

This assay determines the effectiveness of compounds of Formula I in relieving one of the symptoms in an in vivo model of neuropathic pain produced by spinal nerve ligation, namely mechanical allodynia.

Tactile allodynia was induced in rats using the procedures described by Kim and Chung, Pain 50: 355-363 (1992). Briefly, the rats were anesthetized with 2-5% inhaled isoflurane and maintained by 1% isoflurane. Each animal was then placed in a prone position, a 3 cm lateral incision was made, and the left paraspinal muscles separated from the spinous process at the L₄-S₂ level. The L₆ transverse process was then removed in order to visually identify the L₄-L₆ spinal nerves. The L₅ and L₆ spinal nerves were then individually isolated and tightly ligated with silk thread. The wound was then closed in layers by silk sutures. These procedures produced rats which developed a significant increase in sensitivity to mechanical stimuli that did not elicit a response in normal rats.

Mechanical sensitivity was assessed using a procedure described by Chaplan et al., J. Neurosci. Methods 53: 55-63 (1994). Briefly, a series of eight Von Frey filaments of varying rigidity strength were applied to the plantar surface of the hind paw ipsilaterial to the ligations with just enough force to bend the filament. The filaments were held in this position for no more than three seconds or until a positive allodynic response was displayed by the rat. A positive allodynic response consisted of lifting the affected paw followed immediately by licking or shaking of the paw. The order and frequency with which the individual filaments were applied were determined by using Dixon up-down method. Testing was initiated with the middle hair of the series with subsequent filaments being applied in consecutive fashion, either ascending or descending, depending on whether a negative or positive response, respectively, was obtained with the initial filament.

23.2 Thermal Hyperalgesia In vivo Assay

This assay determines the effectiveness of compounds in relieving one of the symptoms of neuropathic pain produced by unilateral mononeuropathy, namely thermal hyperalgesia.

The rats having had surgery as described above were assessed for thermal hyperalgesia sensitivity at least 5-7 days post-surgery. Briefly, the rats were placed beneath inverted plexiglass cages upon an elevated glass platform and a radiant heat source beneath the glass was aimed at the plantar hindpaw. The duration of time before the hindpaw was withdrawn from the floor was measured to the nearest tenth of a second. The cutoff time for the heat stimulus was 40 seconds, and the light was calibrated such that this stimulus duration did not burn or blister the skin. Three latency measurements were taken for each hindpaw ipsilateral to the ligation in each test session, alternating left and right hindpaws, with greater than 1 minute intervals between tests.

23.3 Results

The results show that after oral administration the compounds of the invention produce efficacious anti-allodynic effects at doses less then or equal to 100 mg/kg. The results show that after IV administration the compounds of the invention produce efficacious anti-hyperalgesic effects at doses less than or equal to 30 mg/kg. Overall, the compounds of the present invention were found to be effective in reversing mechanical allodynia-like and thermal hyperalgesia-like symptoms.

Example 24

Example 24 sets forth representative compounds of the invention. compound # name MZ 1 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 423 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 2 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 380 carboxylic acid (pyridin-2-ylmethyl)-amide 3 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 380 carboxylic acid (pyridin-3-ylmethyl)-amide 4 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 380 carboxylic acid (pyridin-4-ylmethyl)-amide 5 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 467 carboxylic acid (2,4,6-trichloro-phenyl)-amide 6 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid 3,4-dichloro-benzylamide 7 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 429 carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide 8 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 461 carboxylic acid [2-(2,4-dichloro-phenyl)-ethyl]-amide 9 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 467 carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amide 10 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 455 carboxylic acid (biphenyl-3-ylmethyl)-amide 11 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 370 carboxylic acid (5-methyl-isoxazol-3-yl)-amide 12 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 355 carboxylic acid (1H-pyrazol-3-yl)-amide 13 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 380 carboxylic acid (4-cyano-2H-pyrazol-3-yl)-amide 14 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 383 carboxylic acid (2-ethyl-2H-pyrazol-3-yl)-amide 15 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 371 carboxylic acid (5-hydroxy-1H-pyrazol-3-yl)-amide 16 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 356 carboxylic acid isoxazol-3-ylamide 17 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 431 carboxylic acid (5-phenyl-2H-pyrazol-3-yl)-amide 18 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 383 carboxylic acid (2,5-dimethyl-2H-pyrazol-3-yl)-amide 19 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 448 carboxylic acid (4-bromo-5-methyl-isoxazol-3-yl)-amide 20 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 445 carboxylic acid (2-methyl-5-phenyl-2H-pyrazol-3-yl)-amide 21 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid (5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol- 3-yl)-amide 22 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 366 carboxylic acid pyridin-3-ylamide 23 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 366 carboxylic acid pyridin-4-ylamide 24 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid 3-trifluoromethyl-benzylamide 25 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid 4-trifluoromethyl-benzylamide 26 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 508 carboxylic acid [2-(3-chloro-4-fluoro-phenyl)-4-cyano- 2H-pyrazol-3-yl]-amide 27 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid (5-bromo-6-methyl-pyridin-2-yl)-amide 28 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 453 carboxylic acid [2-(3,5-dimethoxy-phenyl)-ethyl]-amide 29 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(3,5- 393 dimethoxy-phenyl)-ethyl]-amide 30 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 439 carboxylic acid 2,6-dimethoxy-benzylamide 31 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 2,6- 379 dimethoxy-benzylamide 32 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 432 carboxylic acid [2-(1H-indol-3-yl)-ethyl]-amide 33 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(1H- 372 indol-3-yl)-ethyl]-amide 34 2-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 375 4-carbonyl]-amino}-propionic acid methyl ester 35 2-[(1-Phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]- 315 propionic acid methyl ester 36 2-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 417 4-carbonyl]-amino}-propionic acid methyl ester 37 4-Methyl-2-[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)- 357 amino]-pentanoic acid methyl ester 38 2-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 451 4-carbonyl]-amino}-3-phenyl-propionic acid methyl ester 39 3-Phenyl-2-[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)- 391 amino]-propionic acid methyl ester 40 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 451 carboxylic acid (3-fluoro-5-trifluoromethyl-phenyl)-amide 41 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (3- 391 fluoro-5-trifluoromethyl-phenyl)-amide 42 2-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 490 4-carbonyl]-amino}-3-(1H-indol-3-yl)-propionic acid methyl ester 43 3-(1H-Indol-3-yl)-2-[(1-phenyl-5-propyl-1H-pyrazole-4- 430 carbonyl)-amino]-propionic acid methyl ester 44 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 453 carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide 45 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(3,4- 393 dimethoxy-phenyl)-ethyl]-amide 46 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 399 carboxylic acid (2-thiophen-2-yl-ethyl)-amide 47 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 339 thiophen-2-yl-ethyl)-amide 48 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 369 carboxylic acid (furan-2-ylmethyl)-amide 49 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (furan- 309 2-ylmethyl)-amide 50 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 394 carboxylic acid (2-pyridin-2-yl-ethyl)-amide 51 1-Phenyl-5-propyl-1H-pyazole-4-carboxylic acid (2- 334 pyridin-2-yl-ethyl)-amide 52 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 448 carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide 53 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (1- 388 benzyl-pyrrolidin-3-yl)-amide 54 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 385 carboxylic acid (thiophen-2-ylmethyl)-amide 55 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 325 (thiophen-2-ylmethyl)-amide 56 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 419 carboxylic acid (1H-benzoimidazol-2-ylmethyl)-amide 57 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (1H- 359 benzoimidazol-2-ylmethyl)amide 58 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 400 carboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl)-amide 59 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (1- 340 ethyl-pyrrolidin-2-ylmethyl)-amide 60 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 394 carboxylic acid (2-pyridin-3-yl-ethyl)-amide 61 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 334 pyridin-3-yl-ethyl)-amide 62 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 409 carboxylic acid (2-phenoxy-ethyl)-amide 63 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 349 phenoxy-ethyl)-amide 64 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 414 carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide 65 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [3-(2- 354 oxo-pyrrolidin-1-yl)-propyl]-amide 66 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 395 (biphenyl-3-ylmethyl)-amide 67 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 515 carboxylic acid 3,5-bis-trifluoromethyl-benzylamide 68 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 3,5-bis- 455 trifluoromethyl-benzylamide 69 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 424 carboxylic acid 4-nitro-benzylamide 70 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 4-nitro- 364 benzylamide 71 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 397 carboxylic acid (3-imidazol-1-yl-propyl)-amide 72 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (3-imidazol- 337 1-yl-propyl)-amide 73 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 373 carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide 74 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 313 (tetrahydro-furan-2-ylmethyl)-amide 75 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 385 carboxylic acid cyclohexylmethyl-amide 76 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 325 cyclohexylmethyl-amide 77 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 345 carboxylic acid isobutyl-amide 78 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 285 isobutyl-amide 79 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 405 carboxylic acid indan-1-ylamide 80 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid indan- 345 1-ylamide 81 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 357 carboxylic acid cyclopentylamide 82 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 297 cyclopentylamide 83 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 402 carboxylic acid (2-morpholin-4-yl-ethyl)-amide 84 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2-morpholin- 342 4-yl-ethyl)-amide 85 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 439 carboxylic acid 3,5-dimethoxy-benzylamide 86 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 3,5- 379 dimethoxy-benzylamide 87 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 363 (benzo[1,3]dioxol-5-ylmethyl)-amide 88 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 3- 387 trifluoromethyl-benzylamide 89 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 360 carboxylic acid (2-dimethylamino-ethyl)-amide 90 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 300 dimethylamino-ethyl)-amide 91 {[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 389 carbonyl]-methyl-amino}-acetic acid ethyl ester 92 [Methyl-(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)- 329 amino]-acetic acid ethyl ester 93 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 343 pyrrolidin-1-yl-methanone 94 (1-Phenyl-5-propyl-1H-pyrazol-4-yl)-pyrrolidin-1-yl- 283 methanone 95 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 405 (3,4-dihydro-1H-isoquinolin-2-yl)-methanone 96 (3,4-Dihydro-1H-isoquinolin-2-yl)-(1-phenyl-5-propyl- 345 1H-pyrazol-4-yl)-methanone 97 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid benzyl-ethyl-amide 98 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid benzyl- 347 ethyl-amide 99 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 375 thiomorpholin-4-yl-methanone 100 (1-Phenyl-5-propyl-1H-pyrazol-4-yl)-thiomorpholin-4-yl- 315 methanone 101 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 414 carbonyl]-pyrrolidine-2-carboxylic acid dimethylamide 102 1-(1-Phenyl-5-propyl-1H-pyrazole-4-carbonyl)-pyrrolidine- 354 2-carboxylic acid dimethylamide 103 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 514 carboxylic acid (2-methoxy-benzyl)-(2-pyridin-2-yl- ethyl)-amide 104 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 552 carboxylic acid (3,4-dichloro-benzyl)-(2-pyridin-2-yl- ethyl)-amide 105 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 502 carboxylic acid (4-fluoro-benzyl)-(2-pyridin-2-yl-ethyl)-amide 106 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 498 carboxylic acid (4-methyl-benzyl)-(2-pyridin-2-yl-ethyl)- amide 107 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 552 carboxylic acid (3,4-dichloro-benzyl)-(2-pyridin-3-yl- ethyl)-amide 108 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 543 carboxylic acid (3,4-dimethoxy-benzyl)-(1-phenyl-ethyl)- amide 109 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 446 carboxylic acid (2-cyano-ethyl)-phenethyl-amide 110 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 552 carboxylic acid (3,4-dichloro-benzyl)-(2-pyridin-4-yl- ethyl)-amide 111 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 440 carboxylic acid (5-chloro-benzooxazol-2-yl)-amide 112 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 434 carboxylic acid (3,5-dichloro-pyridin-2-yl)-amide 113 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 400 carboxylic acid (5-chloro-pyridin-2-yl)-amide 114 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid phenethyl-amide 115 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 394 carboxylic acid (2-pyridin-4-yl-ethyl)-amide 116 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 468 carboxylic acid (3-chloro-5-trifluoromethyl-pyridin-2-yl)- amide 117 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 464 carboxylic acid (3-diethylcarbamoyl-phenyl)-amide 118 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 525 carboxylic acid [4-(5-methyl-isoxazol-3-ylsulfamoyl)-phenyl]- amide 119 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 399 carboxylic acid (2-chloro-phenyl)-amide 120 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid (1-ethyl-2-methyl-1H-benzoimidazol-5- yl)-amide 121 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 512 carboxylic acid [4-(6-methyl-benzothiazol-2-yl)phenyl]-amide 122 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 471 carboxylic acid (2-methoxy-biphenyl-4-yl)-amide 123 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 405 carboxylic acid (1H-indazol-6-yl)-amide 124 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 365 carboxylic acid phenylamide 125 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (3- 404 diethylcarbamoyl-phenyl)-amide 126 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [4-(5- 465 methyl-isoxazol-3-ylsulfamoyl)-phenyl]-amide 127 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 339 chloro-phenyl)-amide 128 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (1- 387 ethyl-2-methyl-1H-benzoimidazol-5-yl)-amide 129 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [4-(6- 452 methyl-benzothiazol-2-yl)-phenyl]-amide 130 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 411 methoxy-biphenyl-4-yl)-amide 131 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (1H- 345 indazol-6-yl)-amide 132 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 305 phenylamide 133 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 430 (3-diethylcarbamoyl-phenyl)-amide 134 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 491 [4-(5-methyl-isoxazol-3-ylsulfamoyl)-pheny]-amide 135 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 365 (2-chloro-phenyl)-amide 136 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 413 (1-ethyl-2-methyl-1H-benzoimidazol-5-yl)-amide 137 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 478 [4-(6-methyl-benzothiazol-2-yl)-phenyl]-amide 138 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 437 (2-methoxy-biphenyl-4-yl)-amide 139 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 371 (1H-indazol-6-yl)-amide 140 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 331 phenylamide 141 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 379 carboxylic acid m-tolylamide 142 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 395 carboxylic acid (3-methoxy-phenyl)-amide 143 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 379 carboxylic acid benzylamide 144 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid benzyl-methyl-amide 145 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 409 carboxylic acid 4-methoxy-benzylamide 146 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 424 carboxylic acid 3-nitro-benzylamide 147 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid 3-methyl-benzylamide 148 2-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 527 4-carbonyl]-amino}-3-phenyl-propionic acid benzyl ester 149 2-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 451 4-carbonyl]-amino}-3-phenyl-propionic acid methyl ester 150 2-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 493 4-carbonyl]-amino}-3-phenyl-propionic acid tert-butyl ester 151 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 429 carboxylic acid (2-cyclohexyl-1-hydroxymethyl-ethyl)- amide 152 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 390 carboxylic acid (3-cyano-phenyl)-amide 153 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 422 carboxylic acid 4-dimethylamino-benzylamide 154 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 443 carboxylic acid (3-methanesulfonyl-phenyl)-amide 155 4-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 437 4-carbonyl]-amino}-benzoic acid ethyl ester 156 3-Phenyl-2-[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)- 467 amino]-propionic acid benzyl ester 157 3-Phenyl-2-[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)- 391 amino]-propionic acid methyl ester 158 3-Phenyl-2-[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)- 433 amino]-propionic acid tert-butyl ester 159 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 369 cyclohexyl-1-hydroxymethyl-ethyl)-amide 160 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (3- 330 cyano-phenyl)-amide 161 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 4- 362 dimethylamino-benzylamide 162 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (3- 383 methanesulfonyl-phenyl)-amide 163 4-[(1-Phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]- 377 benzoic acid ethyl ester 164 3-Phenyl-2-[(1-phenyl-5-trifluoromethyl-1H-pyrazole-4- 493 carbonyl)-amino]-propionic acid benzyl ester 165 3-Phenyl-2-[(1-phenyl-5-trifluoromethyl-1H-pyrazole-4- 417 carbonyl)-amino]-propionic acid methyl ester 166 3-Phenyl-2-[(1-phenyl-5-trifluoromethyl-1H-pyrazole-4- 459 carbonyl)-amino]-propionic acid tert-butyl ester 167 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 395 (2-cyclohexyl-1-hydroxymethyl-ethyl)-amide 168 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 356 (3-cyano-phenyl)-amide 169 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 388 4-dimethylamino-benzylamide 170 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 409 (3-methanesulfonyl-phenyl)-amide 171 4-[(1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)- 403 amino]-benzoic acid ethyl ester 172 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 465 carboxylic acid 2-fluoro-5-trifluoromethyl-benzylamide 173 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 461 carboxylic acid [2-(3-trifluoromethyl-phenyl)-ethyl]- amide 174 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 473 (7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)- methanone 175 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 463 carboxylic acid (3-trifluoromethyl-benzyloxy)-amide 176 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid benzylamide 291 177 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid tert- 257 butylamide 178 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 305 phenethyl-amide 179 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 297 cyclohexylmethyl-amide 180 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 269 cyclopentylamide 181 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 367 (biphenyl-3-ylmethyl)-amide 182 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 3,5- 427 bis-trifluoromethyl-benzylamide 183 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 3- 359 trifluoromethyl-benzylamide 184 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 335 (benzo[1,3]dioxol-5-ylmethyl)-amide 185 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 3,4- 359 dichloro-benzylamide 186 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 461 carboxylic acid methyl-(3-trifluoromethyl-benzyl)-amide 187 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 475 carboxylic acid ethyl-(3-trifluoromethyl-benzyl)-amide 188 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 437 carboxylic acid benzo[1,3]dioxol-5-ylmethyl-methyl-amide 189 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 451 carboxylic acid benzo[1,3]dioxol-5-ylmethyl-ethyl-amide 190 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 399 carboxylic acid methyl-thiophen-2-ylmethyl-amide 191 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 413 carboxylic acid ethyl-thiophen-2-ylmethyl-amide 192 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 461 carboxylic acid methyl-(4-trifluoromethyl-benzyl)-amide 193 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 475 carboxylic acid ethyl-(4-trifluoromethyl-benzyl)-amide 194 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 494 carboxylic acid benzo[1,3]dioxol-5-ylmethyl-(2- dimethylamino-ethyl)-amide 195 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 518 carboxylic acid (2-dimethylamino-ethyl)-(3- trifluoromethyl-benzyl)-amide 196 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 390 carboxylic acid benzylamide 197 1-(6-Ethoxy-pyridazin-3-yl)-5-trifluoromethyl-1H- 391 pyrazole-4-carboxylic acid benzylamide 198 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 402 carboxylic acid benzylamide 199 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 390 carboxylic acid benzylamide 200 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 375 carboxylic acid benzylamide 201 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 413 carboxylic acid benzylamide 202 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 413 pyrazole-4-carboxylic acid benzylamide 203 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 345 benzylamide 204 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 356 carboxylic acid tert-butylamide 205 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 347 pyrazole-4-carboxylic acid tert-butylamide 206 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 368 carboxylic acid tert-butylamide 207 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 356 carboxylic acid tert-butylamide 208 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 341 carboxylic acid tert-butylamide 209 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 379 carboxylic acid tert-butylamide 210 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 379 pyrazole-4-carboxylic acid tert-butylamide 211 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 311 tert-butylamide 212 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 404 carboxylic acid phenethyl-amide 213 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 395 pyrazole-4-carboxylic acid phenethyl-amide 214 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 416 carboxylic acid phenethyl-amide 215 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 404 carboxylic acid phenethyl-amide 216 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 389 carboxylic acid phenethyl-amide 217 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 427 carboxylic acid phenethyl-amide 218 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 427 pyrazole-4-carboxylic acid phenethyl-amide 219 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 359 phenethyl-amide 220 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 396 carboxylic acid cyclohexylmethyl-amide 221 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 387 pyrazole-4-carboxylic acid cyclohexylmethyl-amide 222 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 408 carboxylic acid cyclohexylmethyl-amide 223 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 396 carboxylic acid cyclohexylmethyl-amide 224 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 381 carboxylic acid cyclohexylmethyl-amide 225 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 419 carboxylic acid cyclohexylmethyl-amide 226 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 419 pyrazole-4-carboxylic acid cyclohexylmethyl-amide 227 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 351 cyclohexylmethyl-amide 228 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 368 carboxylic acid cyclopentylamide 229 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 359 pyrazole-4-carboxylic acid cyclopentylamide 230 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 380 carboxylic acid cyclopentylamide 231 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 368 carboxylic acid cyclopentylamide 232 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 353 carboxylic acid cyclopentylamide 233 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 391 carboxylic acid cyclopentylamide 234 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 391 pyrazole-4-carboxylic acid cyclopentylamide 235 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 323 cyclopentylamide 236 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 466 carboxylic acid (biphenyl-3-ylmethyl)-amide 237 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 457 pyrazole-4-carboxylic acid (biphenyl-3-ylmethyl)-amide 238 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 478 carboxylic acid (biphenyl-3-ylmethyl)-amide 239 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 466 carboxylic acid (biphenyl-3-ylmethyl)-amide 240 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 451 carboxylic acid (biphenyl-3-ylmethyl)-amide 241 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 489 carboxylic acid (biphenyl-3-ylmethyl)-amide 242 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 489 pyrazole-4-carboxylic acid (biphenyl-3-ylmethyl)-amide 243 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 421 (biphenyl-3-ylmethyl)-amide 244 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 526 carboxylic acid 3,5-bis-trifluoromethyl-benzylamide 245 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 517 pyrazole-4-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide 246 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 538 carboxylic acid 3,5-bis-trifluoromethyl-benzylamide 247 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 526 carboxylic acid 3,5-bis-trifluoromethyl-benzylamide 248 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 511 carboxylic acid 3,5-bis-trifluoromethyl-benzylamide 249 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 549 carboxylic acid 3,5-bis-trifluoromethyl-benzylamide 250 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 549 pyrazole-4-carboxylic acid 3,5-bis-trifluoromethyl- benzylamide 251 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 481 3,5-bis-trifluoromethyl-benzylamide 252 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid 3-trifluoromethyl-benzylamide 253 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 449 pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 254 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 470 carboxylic acid 3-trifluoromethyl-benzylamide 255 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid 3-trifluoromethyl-benzylamide 256 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 443 carboxylic acid 3-trifluoromethyl-benzylamide 257 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 481 carboxylic acid 3-trifluoromethyl-benzylamide 258 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 481 pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 259 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 413 3-trifluoromethyl-benzylamide 260 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 434 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 261 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 425 pyrazole-4-carboxylic acid (benzo[1,3]dioxol-5- ylmethyl)-amide 262 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 446 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 263 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 434 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 264 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 419 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 265 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 457 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 266 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 457 pyrazole-4-carboxylic acid (benzo[1,3]dioxol-5- ylmethyl)-amide 267 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 389 (benzo[1,3]dioxol-5-ylmethyl)-amide 268 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid 3,4-dichloro-benzylamide 269 1-(6-Chloro-pyridazin-3-yl)-5-trifluoromethyl-1H- 449 pyrazole-4-carboxylic acid 3,4-dichloro-benzylamide 270 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 470 carboxylic acid 3,4-dichloro-benzylamide 271 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid 3,4-dichloro-benzylamide 272 1-(4-Methoxy-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 443 carboxylic acid 3,4-dichloro-benzylamide 273 1-(2,5-Dichloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 481 carboxylic acid 3,4-dichloro-benzylamide 274 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 481 pyrazole-4-carboxylic acid 3,4-dichloro-benzylamide 275 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 413 3,4-dichloro-benzylamide 276 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 367 carboxylic acid pyrazin-2-ylamide 277 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 435 carboxylic acid (4,6-dichloro-pyrimidin-2-yl)-amide 278 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 383 carboxylic acid (3-fluoro-phenyl)-amide 279 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 410 carboxylic acid (3-nitro-phenyl)-amide 280 5,6-Dichloro-3-{[1-(4-chloro-phenyl)-5-trifluoromethyl- 493 1H-pyrazole-4-carbonyl]-amino}-pyrazine-2-carboxylic acid methyl ester 281 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 385 carboxylic acid (2-cyclopentyl-ethyl)-amide 282 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid 243 benzylamide 283 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid tert- 209 butylamide 284 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid phenethyl- 257 amide 285 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid 249 cyclohexylmethyl-amide 286 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid 221 cyclopentylamide 287 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid (biphenyl- 319 3-ylmethyl)-amide 288 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid 3,5-bis- 379 trifluoromethyl-benzylamide 289 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid 3- 311 trifluoromethyl-benzylamide 290 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid 287 (benzo[1,3]dioxol-5-ylmethyl)-amide 291 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid 3,4- 311 dichloro-benzylamide 292 [1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 327 pyrrolidin-1-yl-methanone 293 [1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 410 (2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 294 [1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 419 (4-pyridin-2-yl-piperazin-1-yl)-methanone 295 (4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-[1-(4- 476 fluoro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- methanone 296 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid 4-methoxy-benzylamide 297 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 423 carboxylic acid [2-(4-methoxy-phenoxy)-ethyl]-amide 298 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 449 carboxylic acid 3-fluoro-5-trifluoromethyl-benzylamide 299 [1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 356 (4-methyl-piperazin-1-yl)-methanone 300 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 403 carboxylic acid (1,2,3,4-tetrahydro-naphthalen-1-yl)- amide 301 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid [cyclopropyl-(4-methoxy-phenyl)- methyl]-amide 302 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid (2,3-dihydro-benzo[d]imidazo[2,1- b]thiazol-6-yl)-amide 303 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 511 carbonyl]-amino}-3-phenyl-propionic acid benzyl ester 304 4-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 421 carbonyl]-amino}-benzoic acid ethyl ester 305 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 427 carboxylic acid (3-methanesulfonyl-phenyl)-amide 306 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 413 carboxylic acid (2-cyclohexyl-1-hydroxymethyl-ethyl)- amide 307 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 369 carboxylic acid (thiophen-2-ylmethyl)-amide 308 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 353 carboxylic acid (furan-2-ylmethyl)-amide 309 1-[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 384 carbonyl]-piperidine-3-carboxylic acid amide 310 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 389 carboxylic acid (2-phenyl-cyclopropyl)-amide 311 [1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 357 (3-hydroxy-piperidin-1-yl)-methanone 312 4-Phenyl-1-(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)- 398 piperidine-4-carbonitrile 313 1-(5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl)-4- 350 phenyl-piperidine-4-carbonitrile 314 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 457 carboxylic acid (3-methanesulfonyl-phenyl)-methyl-amide 315 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 461 carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-amide 316 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 303 carboxylic acid methylamide 317 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 317 carboxylic acid dimethylamide 318 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid (3-acetyl-phenyl)-amide 319 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 487 carboxylic acid (5-ethanesulfonyl-2-methoxy-phenyl)- amide 320 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 443 carboxylic acid (4-methanesulfonyl-phenyl)-amide 321 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 453 carboxylic acid (1,1-dioxo-1H-1lambda*6*- benzo[b]thiophen-6-yl)-amide 322 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 411 carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide 323 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 411 carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide 324 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 427 carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide 325 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 427 carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 326 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 461 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-amide 327 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 400 carboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl)-amide 328 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 400 carboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl)-amide 329 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(3,4- 323 dimethoxy-phenyl)-ethyl]-amide 330 (5-Chloro-1-methyl-1H-pyrazol-4-yl)-(4-methyl- 242 piperazin-1-yl)-methanone 331 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (1- 257 methyl-hexyl)-amide 332 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid 243 (tetrahydro-furan-2-ylmethyl)-amide 333 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (2- 264 pyridin-2-yl-ethyl)-amide 334 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 427 acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide 335 [1-(4-Chloro-phenyl)-5-propyl-1H-pyrazol-4-yl]-(4- 346 methyl-piperazin-1-yl)-methanone 336 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 361 acid (1-methyl-hexyl)-amide 337 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 347 acid (tetrahydro-furan-2-ylmethyl)-amide 338 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 368 acid (2-pyridin-2-yl-ethyl)-amide 339 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid ethyl- 278 pyridin-4-ylmethyl-amide 340 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid benzyl- 291 isopropyl-amide 341 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (1- 332 benzyl-pyrrolidin-3-yl)-methyl-amide 342 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (3- 272 diethylamino-propyl)-amide 343 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid 2,4- 309 dimethoxy-benzylamide 344 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 382 acid ethyl-pyridin-4-ylmethyl-amide 345 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 395 acid benzyl-isopropyl-amide 346 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 436 acid (1-benzyl-pyrrolidin-3-yl)-methyl-amide 347 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 376 acid (3-diethylamino-propyl)-amide 348 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 413 acid 2,4-dimethoxy-benzylamide 349 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid benzyl- 263 methyl-amide 350 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (3,4- 271 difluoro-phenyl)-amide 351 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (3- 303 trifluoromethyl-phenyl)-amide 352 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid methyl- 250 pyridin-2-yl-amide 353 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (3- 277 phenyl-propyl)-amide 354 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 367 acid benzyl-methyl-amide 355 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 375 acid (3,4-difluoro-phenyl)-amide 356 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 407 acid (3-trifluoromethyl-phenyl)-amide 357 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 354 acid methyl-pyridin-2-yl-amide 358 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 381 acid (3-phenyl-propyl)-amide 359 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (2- 264 pyridin-4-yl-ethyl)-amide 360 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid 293 (benzo[1,3]dioxol-5-ylmethyl)-amide 361 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid 263 phenethyl-amide 362 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (2- 253 ethyl-2H-pyrazol-3-yl)-amide 363 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(3,4- 331 dichloro-phenyl)-ethyl]-amide 364 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 368 acid (2-pyridin-4-yl-ethyl)-amide 365 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 397 acid (benzo[1,3]dioxol-5-ylmethyl)-amide 366 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 367 acid phenethyl-amide 367 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 357 acid (2-ethyl-2H-pyrazol-3-yl)-amide 368 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 435 acid [2-(3,4-dichloro-phenyl)-ethyl]-amide 369 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(3- 331 trifluoromethyl-phenyl)-ethyl]-amide 370 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (2- 269 thiophen-2-yl-ethyl)-amide 371 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(4- 297 chloro-phenyl)-ethyl]-amide 372 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid 3- 317 trifluoromethyl-benzylamide 373 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (3- 313 methanesulfonyl-phenyl)-amide 374 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 435 acid [2-(3-trifluoromethyl-phenyl)-ethyl]-amide 375 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 373 acid (2-thiophen-2-yl-ethyl)-amide 376 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 401 acid [2-(4-chloro-phenyl)-ethyl]-amide 377 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 421 acid 3-trifluoromethyl-benzylamide 378 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 417 acid (3-methanesulfonyl-phenyl)-amide 379 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(1H- 302 indol-3-yl)-ethyl]-amide 380 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(3- 281 fluoro-phenyl)-ethyl]-amide 381 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2- 281 fluoro-phenyl)-ethyl]-amide 382 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (1- 270 ethyl-pyrrolidin-2-ylmethyl)-amide 383 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (1- 270 ethyl-pyrrolidin-2-ylmethyl)-amide 384 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 406 acid [2-(1H-indol-3-yl)-ethyl]-amide 385 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 385 acid [2-(3-fluoro-phenyl)-ethyl]-amide 386 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 385 acid [2-(2-fluoro-phenyl)-ethyl]-amide 387 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 374 acid (1-ethyl-pyrrolidin-2-ylmethyl)-amide 388 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 374 acid (1-ethyl-pyrrolidin-2-ylmethyl)-amide 389 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid 2,6- 309 dimethoxy-benzylamide 390 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(3- 297 chloro-phenyl)-ethyl]-amide 391 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(3,5- 323 dimethoxy-phenyl)-ethyl]-amide 392 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (5- 270 chloro-pyridin-2yl)-amide 393 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (2- 277 phenyl-propyl)-amide 394 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 413 acid 2,6-dimethoxy-benzylamide 395 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 401 acid [2-(3-chloro-phenyl)-ethyl]-amide 396 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 427 acid [2-(3,5-dimethoxy-phenyl)-ethyl]-amide 397 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 374 acid (5-chloro-pyridin-2-yl)-amide 398 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 381 acid (2-phenyl-propyl)-amide 399 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(4- 281 fluoro-phenyl)-ethyl]-amide 400 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4- 331 dichloro-phenyl)-ethyl]-amide 401 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid 325 (biphenyl-3-ylmethyl)-amide 402 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid 236 pyridin-4-ylamide 403 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (3- 375 benzenesulfonyl-phenyl)-amide 404 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 385 acid [2-(4-fluoro-phenyl)-ethyl]-amide 405 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 435 acid [2-(2,4-dichloro-phenyl)-ethyl]-amide 406 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 429 acid (biphenyl-3-ylmethyl)-amide 407 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 340 acid pyridin-4-ylamide 408 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 479 acid (3-benzenesulfonyl-phenyl)-amide 409 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 425 carboxylic acid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide 410 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 381 carboxylic acid (3-hydroxy-phenyl)-amide 411 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 411 carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide 412 5-Trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1H- 495 pyrazole-4-carboxylic acid [2-(2,4-dichloro-phenyl)- ethyl]-amide 413 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 461 carboxylic acid (2-fluoro-5-methanesulfonyl-phenyl)- amide 414 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 427 carboxylic acid [2-(2-chloro-phenyl)-ethyl]-amide 415 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 409 carboxylic acid [2-(4-hydroxy-phenyl)-ethyl]-amide 416 1-(3-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid 3-trifluoromethyl-benzylamide 417 1-(4-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 454 carboxylic acid (3-methanesulfonyl-phenyl)-amide 418 1-(4-Amino-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 424 carboxylic acid (3-methanesulfonyl-phenyl)-amide 419 1-(2,5-Dichloro-phenyl)-1H-pyrazole-4-carboxylic acid 393 [2-(3-chloro-phenyl)-ethyl]-amide 420 1-(2-Nitro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 438 carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide 421 1-Benzothiazol-2-yl-5-trifluoromethyl-1H-pyrazole-4- 450 carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide 422 1-(4-Nitro-phenyl)-5-trifiuoromethyl-1H-pyrazole-4- 438 carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide 423 1-(4-Amino-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 408 carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide 424 1-(4-Guanidino-phenyl)-5-trifiuoromethyl-1H-pyrazole-4- 466 carboxylic acid (3-methanesulfonyl-phenyl)-amide 425 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 393 [2-(2-chloro-phenyl)-ethyl]-amide 426 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 393 [2-(3-chloro-phenyl)-ethyl]-amide 427 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 393 [2-(4-chloro-phenyl)-ethyl]-amide 428 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 427 [2-(2,4-dichloro-phenyl)-ethyl]-amide 429 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 427 [2-(3,4-dichloro-phenyl)-ethyl]-amide 430 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 427 [2 (2,6-dichloro-phenyl)-ethyl]-amide 431 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 377 [2-(2-fluoro-phenyl)-ethyl]-amide 432 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 377 [2-(3-fluoro-phenyl)-ethyl]-amide 433 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 377 [2-(4-fluoro-phenyl)-ethyl]-amide 434 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 427 [2-(3-trifluoromethyl-phenyl)-ethyl]-amide 435 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 387 [2-(4-ethyl-phenyl)-ethyl]-amide 436 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 419 [2-(3,5-dimethoxy-phenyl)-ethyl]-amide 437 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 419 [2-(3,4-dimethoxy-phenyl)-ethyl]-amide 438 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 365 (2-thiophen-2-yl-ethyl)-amide 439 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 363 4-fluoro-benzylamide 440 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 379 2-chloro-benzylamide 441 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 379 4-chloro-benzylamide 442 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 359 3-methyl-benzylamide 443 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 359 4-methyl-benzylamide 444 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 413 4-trifluoromethyl-benzylamide 445 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 431 3-fluoro-5-trifluoromethyl-benzylamide 446 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 409 carboxylic acid [2-(3-hydroxy-phenyl)-ethyl]-amide 447 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 375 [2-(3-hydroxy-phenyl)-ethyl]-amide 448 1-(3-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid (3- 375 methanesulfonyl-phenyl)-amide 449 1-(3-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid [2-(3- 359 chloro-phenyl)-ethyl]-amide 450 1-(3-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid [2- 393 (2,6-dichloro-phenyl)-ethyl]-amide 451 1-(4-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid (3- 375 methanesulfonyl-phenyl)-amide 452 1-(4-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid [2-(3- 359 chloro-phenyl)-ethyl]-amide 453 1-(4-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid [2- 393 (2,6-dichloro-phenyl)-ethyl]-amide 454 1-Benzyl-1H-pyrazole-4-carboxylic acid (3- 355 methanesulfonyl-phenyl)-amide 455 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(3-chloro- 339 phenyl)-ethyl]-amide 456 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(2,6-dichloro- 373 phenyl)-ethyl]-amide 457 1-p-Tolyl-1H-pyrazole-4-carboxylic acid (3- 355 methanesulfonyl-phenyl)-amide 458 1-p-Tolyl-1H-pyrazole-4-carboxylic acid [2-(3-chloro- 339 phenyl)-ethyl]-amide 459 1-p-Tolyl-1H-pyrazole-4-carboxylic acid [2-(2,6-dichloro- 373 phenyl)-ethyl]-amide 460 1-(2-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid (3- 375 methanesulfonyl-phenyl)-amide 461 1-(2-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid [2-(3- 359 chloro-phenyl)-ethyl]-amide 462 1-(2-Chloro-phenyl)-1H-pyrazole-4-carboxylic acid [2- 393 (2,6-dichloro-phenyl)-ethyl]-amide 463 1-(3,4-Dichloro-phenyl)-1H-pyrazole-4-carboxylic acid 409 (3-methanesulfonyl-phenyl)-amide 464 1-(3,4-Dichloro-phenyl)-1H-pyrazole-4-carboxylic acid 393 [2-(3-chloro-phenyl)-ethyl]-amide 465 1-(3,4-Dichloro-phenyl)-1H-pyrazole-4-carboxylic acid 427 [2-(2,6-dichloro-phenyl)-ethyl]-amide 466 1-(4-Bromo-phenyl)-1H-pyrazole-4-carboxylic acid (3- 419 methanesulfonyl-phenyl)-amide 467 1-(4-Bromo-phenyl)-1H-pyrazole-4-carboxylic acid [2-(3- 403 chloro-phenyl)-ethyl]-amide 468 1-(4-Bromo-phenyl)-1H-pyrazole-4-carboxylic acid [2- 437 (2,6-dichloro-phenyl)-ethyl]-amide 469 1-(4-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid (3- 359 methanesulfonyl-phenyl)-amide 470 1-(4-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid [2-(3- 343 chloro-phenyl)-ethyl]-amide 471 1-(4-Fluoro-phenyl)-1H-pyrazole-4-carboxylic acid [2- 377 (2,6-dichloro-phenyl)-ethyl]-amide 472 1-(4-Methoxy-phenyl)-1H-pyrazole-4-carboxylic acid (3- 371 methanesulfonyl-phenyl)-amide 473 1-(4-Methoxy-phenyl)-1H-pyrazole-4-carboxylic acid [2- 355 (3-chloro-phenyl)-ethyl]-amide 474 1-(4-Methoxy-phenyl)-1H-pyrazole-4-carboxylic acid [2- 389 (2,6-dichloro-phenyl)-ethyl]-amide 475 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 391 [2-(3,4-dihydroxy-phenyl)-ethyl]-amide 476 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 375 [2-(4-hydroxy-phenyl)-ethyl]-amide 477 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 363 carboxylic acid benzylamide 478 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 377 carboxylic acid phenethyl-amide 479 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 411 carboxylic acid [2-(2-chloro-phenyl)-ethyl]-amide 480 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 411 carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide 481 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 411 carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 482 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 445 carboxylic acid [2-(2,4-dichloro-phenyl)-ethyl]-amide 483 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 445 carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-amide 484 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 445 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-amide 485 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 395 carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide 486 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 395 carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide 487 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 395 carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide 488 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 445 carboxylic acid [2-(3-trifluoromethyl-phenyl)-ethyl]- amide 489 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid (2-trifluoromethyl-phenyl)-amide 490 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 401 carboxylic acid (2,4-difluoro-phenyl)-amide 491 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid (4-isopropyl-phenyl)-amide 492 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 451 carboxylic acid (2-fluoro-5-trifluoromethyl-phenyl)-amide 493 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 405 carboxylic acid (2-isopropenyl-phenyl)-amide 494 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid (4-ethyl-phenyl)-amide 495 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 451 carboxylic acid (2-fluoro-3-trifluoromethyl-phenyl)-amide 496 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 449 carboxylic acid (2-trifluoromethoxy-phenyl)-amide 497 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid (2,5-dimethyl-phenyl)-amide 498 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 419 carboxylic acid (2,3,4-trifluoro-phenyl)-amide 499 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 383 carboxylic acid (2-fluoro-phenyl)-amide 500 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 421 carboxylic acid (4-tert-butyl-phenyl)-amide 501 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 467 carboxylic acid (2-chloro-5-trifluoromethyl-phenyl)-amide 502 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid (3-trifluoromethyl-phenyl)-amide 503 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 379 carboxylic acid o-tolylamide 504 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid (2,4-dimethyl-phenyl)-amide 505 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 421 carboxylic acid (2-tert-butyl-phenyl)-amide 506 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid (2,6-dimethyl-phenyl)-amide 507 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 409 carboxylic acid (4-ethoxy-phenyl)-amide 508 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 400 carboxylic acid (2-chloro-pyridin-3-yl)-amide 509 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid (2,4-dichloro-phenyl)-amide 510 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 441 carboxylic acid biphenyl-4-ylamide 511 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 413 carboxylic acid (5-chloro-2-methyl-phenyl)-amide 512 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 399 carboxylic acid (4-chloro-phenyl)-amide 513 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 390 carboxylic acid (4-cyano-phenyl)-amide 514 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- carboxylic acid (3-benzenesulfonyl-phenyl)-amide 515 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 471 carboxylic acid (4-methoxy-biphenyl-3-yl)-amide 516 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 450 carboxylic acid (4-morpholin-4-yl-phenyl)-amide 517 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid (4-trifluoromethyl-phenyl)-amide 518 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 450 carboxylic acid [4-(ethyl-isopropyl-amino)-phenyl]-amide 519 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 413 carboxylic acid (2-chloro-5-methyl-phenyl)-amide 520 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 448 carboxylic acid (2-piperidin-1-yl-phenyl)-amide 521 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 408 carboxylic acid (4-dimethylamino-phenyl)-amide 522 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 409 carboxylic acid (5-methoxy-2-methyl-phenyl)-amide 523 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid (4-methyl-2-oxo-2H-chromen-7-yl)-amide 524 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 429 carboxylic acid (2-chloro-5-methoxy-phenyl)-amide 525 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 416 carboxylic acid quinolin-8-ylamide 526 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 430 carboxylic acid (2-pyrrol-1-yl-phenyl)-amide 527 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 480 carboxylic acid [2-(1H-indol-2-yl)-phenyl]-amide 528 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 404 carboxylic acid (3-cyanomethyl-phenyl)-amide 529 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 541 carboxylic acid [5-chloro-2-(4-chloro-phenylsulfanyl)- phenyl]-amide 530 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 390 carboxylic acid (2-cyano-phenyl)-amide 531 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 409 carboxylic acid (4-methoxy-phenyl)-methyl-amide 532 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 395 carboxylic acid (4-methoxy-phenyl)-amide 533 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 434 carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide 534 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 467 carboxylic acid (2-chloro-4-trifluoromethyl-phenyl)-amide 535 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 397 carboxylic acid (5-fluoro-2-methyl-phenyl)-amide 536 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 386 carboxylic acid (3-methyl-isothiazol-5-yl)-amide 537 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 372 carboxylic acid thiazol-2-ylamide 538 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 432 carboxylic acid (5-phenyl-oxazol-2-yl)-amide 539 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid (1,1-dioxo-tetrahydro-1lambda*6*- thiophen-3-yl)-amide 540 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 402 carboxylic acid (5-methylsulfanyl-1H-[1,2,4]triazol-3-yl)- amide 541 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 356 carboxylic acid (1H-[1,2,4]triazol-3-yl)-amide 542 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 441 carboxylic acid (5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)- amide 543 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 370 carboxylic acid (3-methyl-isoxazol-5-yl)-amide 544 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 448 carboxylic acid (4-phenyl-thiazol-2-yl)-amide 545 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 422 carboxylic acid benzothiazol-2-ylamide 546 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 405 carboxylic acid (1H-benzoimidazol-2-yl)-amide 547 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid 3-methoxy-benzylamide 548 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid 2-methoxy-benzylamide 549 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 377 carboxylic acid 3-methyl-benzylamide 550 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 377 carboxylic acid 4-methyl-benzylamide 551 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 397 carboxylic acid 2-chloro-benzylamide 552 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 431 carboxylic acid 3,4-dichloro-benzylamide 553 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 423 carboxylic acid 2,4-dimethoxy-benzylamide 554 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 423 carboxylic acid 2,3-dimethoxy-benzylamide 555 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 397 carboxylic acid 4-chloro-benzylamide 556 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 369 carboxylic acid cyclohexylmethyl-amide 557 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 431 carboxylic acid 2,4-dichloro-benzylamide 558 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 489 carboxylic acid 3-iodo-benzylamide 559 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 381 carboxylic acid 2-fluoro-benzylamide 560 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 431 carboxylic acid 4-trifluoromethyl-benzylamide 561 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 357 carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide 562 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 563 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 449 carboxylic acid 2-fluoro-5-trifluoromethyl-benzylamide 564 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 431 carboxylic acid 3-trifluoromethyl-benzylamide 565 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 499 carboxylic acid 3,5-bis-trifluoromethyl-benzylamide 566 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 423 carboxylic acid 2,6-dimethoxy-benzylamide 567 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 423 carboxylic acid 3,5-dimethoxy-benzylamide 568 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 377 carboxylic acid (1-phenyl-ethyl)-amide 569 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 364 carboxylic acid (pyridin-2-ylmethyl)-amide 570 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 455 carboxylic acid [2-(4-bromo-phenyl)-ethyl]amide 571 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-amide 572 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 437 carboxylic acid [2-(3,5-dimethoxy-phenyl)-ethyl]-amide 573 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 437 carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide 574 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 391 carboxylic acid (2-o-tolyl-ethyl)-amide 575 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 405 carboxylic acid [2-(3,4-dimethyl-phenyl)-ethyl]-amide 576 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 405 carboxylic acid [2-(2,4-dimethyl-phenyl)-ethyl]-amide 577 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 405 carboxylic acid (4-phenyl-butyl)-amide 578 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 393 carboxylic acid [2-(4-hydroxy-phenyl)-ethyl]-amide 579 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 383 carboxylic acid (2-chloro-phenyl)-amide 580 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 363 carboxylic acid o-tolylamide 581 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 363 carboxylic acid m-tolylamide 582 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 379 carboxylic acid (2-methoxy-phenyl)-amide 583 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 367 carboxylic acid (3-fluoro-phenyl)-amide 584 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 385 carboxylic acid (2,4-difluoro-phenyl)-amide 585 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 449 carboxylic acid (3-trifluoromethoxy-phenyl)-amide 586 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 399 (2-trifluoromethyl-phenyl)-amide 587 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 407 acid (2-trifluoromethyl-phenyl)-amide 588 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 373 trifluoromethyl-phenyl)-amide 589 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 366 (2-chloro-pyridin-3-yl)-amide 590 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 374 acid (2-chloro-pyridin-3-yl)-amide 591 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 340 chloro-pyridin-3-yl)-amide 592 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 373 (4-isopropyl-phenyl)-amide 593 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 381 acid (4-isopropyl-phenyl)-amide 594 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (4- 347 isopropyl-phenyl)-amide 595 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 365 (4-chloro-phenyl)-amide 596 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 373 acid (4-chloro-phenyl)-amide 597 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (4- 339 chloro-phenyl)-amide 598 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 359 (4-ethyl-phenyl)-amide 599 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 367 acid (4-ethyl-phenyl)-amide 600 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (4- 333 ethyl-phenyl)-amide 601 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 356 (4-cyano-phenyl)-amide 602 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 364 acid (4-cyano-phenyl)-amide 603 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (4- 330 cyano-phenyl)-amide 604 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 415 (2-trifluoromethoxy-phenyl)-amide 605 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 423 acid (2-trifluoromethoxy-phenyl)-amide 606 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 389 trifluoromethoxy-phenyl)-amide 607 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 416 (4-morpholin-4-yl-phenyl)-amide 608 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 424 acid (4-morpholin-4-yl-phenyl)-amide 609 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (4- 390 morpholin-4-yl-phenyl)-amide 610 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 349 (2-fluoro-phenyl)-amide 611 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 357 acid (2-fluoro-phenyl)-amide 612 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 323 fluoro-phenyl)-amide 613 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 399 (4-trifluoromethyl-phenyl)-amide 614 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 407 acid (4-trifluoromethyl-phenyl)-amide 615 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (4- 373 trifluoromethyl-phenyl)-amide 616 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 399 (3-trifluoromethyl-phenyl)-amide 617 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (3- 373 trifluoromethyl-phenyl)-amide 618 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 414 (2-piperidin-1-yl-phenyl)-amide 619 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 422 acid (2-piperidin-1-yl-phenyl)-amide 620 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2- 388 piperidin-1-yl-phenyl)-amide 621 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 345 o-tolylamide 622 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 353 acid o-tolylamide 623 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid o- 319 tolylamide 624 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 382 quinolin-8-ylamide 625 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 390 acid quinolin-8-ylamide 626 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid 356 quinolin-8-ylamide 627 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 375 (4-ethoxy-phenyl)-amide 628 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 383 acid (4-ethoxy-phenyl)-amide 629 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (4- 349 ethoxy-phenyl)-amide 630 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 437 [2-(4-bromo-phenyl)-ethyl]-amide 631 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 445 acid [2-(4-bromo-phenyl)-ethyl]-amide 632 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(4- 411 bromo-phenyl)-ethyl]-amide 633 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 387 [2-(3,4-dimethyl-phenyl)-ethyl]-amide 634 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 395 acid [2-(3,4-dimethyl-phenyl)-ethyl]-amide 635 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(3,4- 361 dimethyl-phenyl)-ethyl]-amide 636 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(3- 367 chloro-phenyl)-ethyl]-amide 637 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 389 [2-(2-methoxy-phenyl)-ethyl]-amide 638 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 397 acid [2-(2-methoxy-phenyl)-ethyl]-amide 639 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(2- 363 methoxy-phenyl)-ethyl]-amide 640 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(3- 351 fluoro-phenyl)-ethyl]-amide 641 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(3,4- 401 dichloro-phenyl)-ethyl]-amide 642 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(4- 367 chloro-phenyl)-ethyl]-amide 643 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 435 acid [2-(2,6-dichloro-phenyl)-ethyl]-amide 644 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(2,6- 401 dichloro-phenyl)-ethyl]-amide 645 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 389 [2-(3-methoxy-phenyl)-ethyl]-amide 646 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 397 acid [2-(3-methoxy-phenyl)-ethyl]-amide 647 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(3- 363 methoxy-phenyl)-ethyl]-amide 648 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 373 (2-o-tolyl-ethyl)-amide 649 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 381 acid (2-o-tolyl-ethyl)-amide 650 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (2-o- 347 tolyl-ethyl)-amide 651 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 375 (2-phenoxy-ethyl)-amide 652 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 383 acid (2-phenoxy-ethyl)-amide 653 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 387 (4-phenyl-butyl)-amide 654 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 395 acid (4-phenyl-butyl)-amide 655 1-Phenyl-5-propyl-1H-pyrazole-4-caxboxylic acid (4- 361 phenyl-butyl)-amide 656 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 385 (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide 657 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 393 acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide 658 1-Phenyl-5-propyl-1H-pyrazole-4-caxboxylic acid 359 (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide 659 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 387 [2-(2,4-dimethyl-phenyl)-ethyl]-amide 660 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 395 acid [2-(2,4-dimethyl-phenyl)-ethyl]-amide 661 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [2-(2,4- 361 dimethyl-phenyl)-ethyl]-amide 662 1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 371 indan-1-ylamide 663 1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carboxylic 379 acid indan-1-ylamide 664 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 471 carboxylic acid [2-(4-bromo-phenyl)-ethyl]-amide 665 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 423 carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-amide 666 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid (2-o-tolyl-ethyl)-amide 667 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 421 carboxylic acid (4-phenyl-butyl)-amide 668 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 421 carboxylic acid [2-(2,4-dimethyl-phenyl)-ethyl]-amide 669 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 421 carboxylic acid [2-(3,4-dimethyl-phenyl)-ethyl]-amide 670 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 423 carboxylic acid [2-(2-methoxy-phenyl)-ethyl]-amide 671 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 419 carboxylic acid (1,2,3,4-tetrahydro-naphthalen-1-yl)- amide 672 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 449 carboxylic acid (2,4,6-triethyl-phenyl)-amide 673 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid (2-ethyl-6-methyl-phenyl)-amide 674 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid (2,4,6-trimethyl-phenyl)-amide 675 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 421 carboxylic acid (2,6-diethyl-phenyl)-amide 676 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 501 carboxylic acid (2,5-bis-trifluoromethyl-phenyl)-amide 677 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 449 carboxylic acid (2,6-diisopropyl-phenyl)-amide 678 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 421 carboxylic acid (2-isopropyl-6-methyl-phenyl)-amide 679 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 494 carboxylic acid (2,4,6-triethyl-3-nitro-phenyl)-amide 680 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 401 carboxylic acid (3,4-difluoro-phenyl)-amide 681 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 477 carboxylic acid (2,5-di-tert-butyl-phenyl)-amide 682 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 455 carboxylic acid (3-chloro-2,6-diethyl-phenyl)-amide 683 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid (4-cyclohexyl-phenyl)-amide 684 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 521 carboxylic acid (2,5-dibromo-phenyl)-amide 685 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid (2-isopropyl-phenyl)-amide 686 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 4- 325 chloro-benzylamide 687 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 2- 325 chloro-benzylamide 688 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 2- 309 fluoro-benzylamide 689 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 4- 309 fluoro-benzylamide 690 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (2- 311 chloro-phenyl)-amide 691 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (3- 311 chloro-phenyl)-amide 692 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (4- 311 chloro-phenyl)-amide 693 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 321 carboxylic acid benzylamide 694 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 335 carboxylic acid phenethyl-amide 695 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 365 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 696 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 355 carboxylic acid 4-chloro-benzylamide 697 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 355 carboxylic acid 2-chloro-benzylamide 698 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 339 carboxylic acid 2-fluoro-benzylamide 699 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 339 carboxylic acid 4-fluoro-benzylamide 700 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 341 carboxylic acid (2-chloro-phenyl)-amide 701 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 341 carboxylic acid (3-chloro-phenyl)-amide 702 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 341 carboxylic acid (4-chloro-phenyl)-amide 703 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 277 phenylamide 704 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 292 (pyridin-3-ylmethyl)-amide 705 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 307 carboxylic acid phenylamide 706 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 322 carboxylic acid (pyridin-3-ylmethyl)-amide 707 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 309 acid benzylamide 708 1-Benzyl-1H-pyrazole-4-carboxylic acid benzylamide 291 709 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 341 acid [2-(2-fluoro-phenyl)-ethyl]-amide 710 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(2-fluoro- 323 phenyl)-ethyl]-amide 711 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(2-fluoro- 323 phenyl)-ethyl]-amide 712 1-Benzyl-1H-pyrazole-4-carboxylic acid phenethyl-amide 305 713 1-Benzyl-1H-pyrazole-4-carboxylic acid phenethyl-amide 341 714 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(3-fluoro- 323 phenyl)-ethyl]-amide 715 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 353 acid (benzo[1,3]dioxol-5-ylmethyl)-amide 716 1-Benzyl-1H-pyrazole-4-carboxylic acid 335 (benzo[1,3]dioxol-5-ylmethyl)-amide 717 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 341 acid [2-(4-fluoro-phenyl)-ethyl]-amide 718 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(4-fluoro- 323 phenyl)-ethyl]-amide 719 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 343 acid 4-chloro-benzylamide 720 1-Benzyl-1H-pyrazole-4-carboxylic acid 4-chloro- 325 benzylamide 721 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 357 acid [2-(3-chloro-phenyl)-ethyl]-amide 722 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 343 acid 2-chloro-benzylamide 723 1-Benzyl-1H-pyrazole-4-carboxylic acid 2-chloro- 325 benzylamide 724 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 357 acid [2-(4-chloro-phenyl)-ethyl]-amide 725 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(4-chloro- 339 phenyl)-ethyl]-amide 726 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 327 acid 2-fluoro-benzylamide 727 1-Benzyl-1H-pyrazole-4-carboxylic acid 2-fluoro- 309 benzylamide 728 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 353 acid [2-(2-methoxy-phenyl)-ethyl]-amide 729 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(2-methoxy- 335 phenyl)-ethyl]-amide 730 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 327 acid 4-fluoro-benzylamide 731 1-Benzyl-1H-pyrazole-4-carboxylic acid 4-fluoro- 309 benzylamide 732 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 353 acid [2-(3-methoxy-phenyl)-ethyl]-amide 733 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(3-methoxy- 335 phenyl)-ethyl]-amide 734 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 310 acid (pyridin-3-ylmethyl)-amide 735 1-Benzyl-1H-pyrazole-4-carboxylic acid (pyridin-3- 292 ylmethyl)-amide 736 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 391 acid [2-(3-trifluoromethyl-phenyl)-ethyl]-amide 737 1-Benzyl-1H-pyrazole-4-carboxylic acid [2-(3- 373 trifluoromethyl-phenyl)-ethyl]-amide 738 N-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 395 yl]-3-methoxy-benzamide 739 N-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 443 yl]-3-methanesulfonyl-benzamide 740 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (3- 355 methanesulfonyl-phenyl)-amide 741 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 385 carboxylic acid (3-methanesulfonyl-phenyl)-amide 742 1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic 373 acid (3-methanesulfonyl-phenyl)-amide 743 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid (5,6-dimethyl-1H-benzoimidazol-2-yl)- amide 744 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 419 carboxylic acid (1-methyl-1H-benzoimidazol-2-yl)-amide 745 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 419 carboxylic acid (1H-benzoimidazol-2-yl)-methyl-amide 746 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (4-tert- 333 butyl-phenyl)-amide 747 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [2- 373 (2,4-dichloro-phenyl)-ethyl]-amide 748 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (4- 333 phenyl-butyl)-amide 749 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [2- 333 (2,4-dimethyl-phenyl)-ethyl]-amide 750 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [2-(2- 339 chloro-phenyl)-ethyl]-amide 751 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (4- 319 isopropyl-phenyl)-amide 752 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (2-o- 319 tolyl-ethyl)-amide 753 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [2-(4- 339 chloro-phenyl)-ethyl]-amide 754 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 403 carboxylic acid [2-(2,4-dichloro-phenyl)-ethyl]-amide 755 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 363 carboxylic acid (4-phenyl-butyl)-amide 756 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 363 carboxylic acid [2-(2,4-dimethyl-phenyl)-ethyl]-amide 757 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 369 carboxylic acid [2-(2-chloro-phenyl)-ethyl]-amide 758 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 349 carboxylic acid (4-isopropyl-phenyl)-amide 759 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 349 carboxylic acid (2-o-tolyl-ethyl)-amide 760 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 369 carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 761 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (2- 342 pyrrol-1-yl-phenyl)-amide 762 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (2- 361 trifluoromethoxy-phenyl)-amide 763 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid 328 quinolin-8-ylamide 764 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 363 carboxylic acid (4-tert-butyl-phenyl)-amide 765 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 372 carboxylic acid (2-pyrrol-1-yl-phenyl)-amide 766 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 391 carboxylic acid (2-trifluoromethoxy-phenyl)-amide 767 1-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole-4- 358 carboxylic acid quinolin-8-ylamide 768 N-[5-(4-Chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]- 311 benzamide 769 N-(2-Methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-benzamide 283 770 N-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-benzamide 241 771 N-(2-Methyl-5-phenyl-2H-pyrazol-3-yl)-benzamide 277 772 N-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 365 yl]-benzamide 773 N-[5-(4-Chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-3- 329 fluoro-benzamide 774 N-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-3-fluoro- 259 benzamide 775 N-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 383 yl]-3-fluoro-benzamide 776 N-[5-(4-Chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-2- 341 methoxy-benzamide 777 2-Methoxy-N-(2-methyl-5-thiophen-2-yl-2H-pyrazol-3- 313 yl)-benzamide 778 N-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-2-methoxy- 271 benzamide 779 2-Methoxy-N-(2-methyl-5-phenyl-2H-pyrazol-3-yl)- 307 benzamide 780 N-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 395 yl]-2-methoxy-benzamide 781 N-[5-(4-Chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-3- 389 methanesulfonyl-benzamide 782 N-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-3- 319 methanesulfonyl-benzamide 783 3-Methanesulfonyl-N-(2-methy-5-phenyl-2H-pyrazol-3- 355 yl)-benzamide 784 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 458 yl]-3-(3-methanesulfonyl-phenyl)-urea 785 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 411 carbamic acid 2-methoxy-phenyl ester 786 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 487 carboxylic acid (1-methyl-5-trifluoromethyl-1H- benzoimidazol-2-yl)-amide 787 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 437 carboxylic acid (5-fluoro-1-methyl-1H-benzoimidazol-2- yl)-amide 788 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid (1,6-dimethyl-1H-benzoimidzol-2-yl)- amide 789 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 487 carboxylic acid (5,6-dichloro-1-methyl-1H- benzoimidazol-2-yl)-amide 792 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 475 carboxylic acid [2-(2,4-dichloro-phenyl)-ethyl]-methyl- amide 793 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 414 carboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl)-methyl- amide 794 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 425 carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-methyl-amide 795 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 475 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-methyl- amide 796 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 441 carboxylic acid [2-(2-chloro-phenyl)-ethyl]-methyl-amide 797 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 425 carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-methyl-amide 798 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 425 carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-methyl-amide 799 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 441 carboxylic acid [2-(3-chloro-phenyl)-ethyl]-methyl-amide 800 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 501 carboxylic acid (5-ethanesulfonyl-2-methoxy-phenyl)- methyl-amide 801 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 441 carboxylic acid [2-(4-chloro-phenyl)-ethyl]-methyl-amide 802 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 475 carboxylic acid (2-fluoro-5-methanesulfonyl-phenyl)- methyl-amide 803 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 463 carboxylic acid methyl-(3-trifluoromethoxy-phenyl)- amide 804 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 437 carboxylic acid [2-(4-methoxy-phenyl)-ethyl]-methyl- amide 805 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 483 carboxylic acid benzyl-(1-phenyl-ethyl)-amide 806 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid methyl-phenethyl-amide 807 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 471 carboxylic acid bis-pyridin-3-ylmethyl-amide 808 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 471 carboxylic acid bis-pyridin-2-ylmethyl-amide 809 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid (2-cyano-ethyl)-pyridin-3-ylmethyl-amide 810 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 435 (4-pyridin-2-yl-piperazin-1-yl)-methanone 811 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 435 carboxylic acid isopropyl-phenethyl-amide 812 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 483 carboxylic acid benzyl-(1-phenyl-ethyl)-amide 813 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 408 carboxylic acid ethyl-pyridin-4-ylmethy-amide 814 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 341 (2,5-dihydro-pyrrol-1-yl)-methanone 815 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 361 thiazolidin-3-yl-methanone 816 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 439 carboxylic acid ethyl-(5-nitro-pyridin-2-yl)-amide 817 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 416 carboxylic acid quinolin-6-ylamide 818 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 466 carboxylic acid (4-nitro-benzyl)-propyl-amide 819 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 446 [3-(4-methoxy-phenyl)-pyrazol-1-yl]-methanone 820 [1(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 426 (4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 821 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 414 yl]-3-(3-fluoro-phenyl)-thiourea 822 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 432 yl]-3-(2,5-difluoro-phenyl)-thiourea 823 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 448 yl]-3-(3,4-dichloro-phenyl)-urea 824 1-[1-(4-Chloro-cyclohexa-2,4-dienyl)-5-trifluoromethyl- 464 1H-pyrazol-4-yl]-3-(4-trifluoromethyl-phenyl)-thiourea 825 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 464 yl]-3-(2,4-dichloro-phenyl)-thiourea 826 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 411 carbamic acid 4-methoxy-phenyl ester 827 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 381 carbamic acid phenyl ester 828 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 361 carbamic acid isobutyl ester 829 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 464 yl]-3-(2,6-diisopropyl-phenyl)-urea 830 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 347 carbamic acid propyl ester 832 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 410 carboxylic acid (3-methanesulfonyl-phenyl)-amide 833 5-Trifluoromethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H- 482 pyrazole-4-carboxylic acid 4-trifluoromethyl-benzylamide 834 5-Trifluoromethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H- 446 pyrazole-4-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]- amide 835 5-Trifluoromethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H- 440 pyrazole-4-carboxylic acid (1H-benzoimidazol-2-yl)- amide 836 5-Trifluoromethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H- 401 pyrazole-4-carboxylic acid pyridin-4-ylamide 837 5-Trifluoromethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H- 478 pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl)- amide 838 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 448 4-carboxylic acid 4-trifluoromethyl-benzylamide 839 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 412 4-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide 840 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 406 4-carboxylic acid (1H-benzoimidazol-2-yl)-amide 841 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 367 4-carboxylic acid pyridin-4-ylamide 842 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 444 4-carboxylic acid (3-methanesulfonyl-phenyl)-amide 843 1-(6-Hydroxy-pyridazin-3-yl)-5-trifluoromethyl-1H- 427 pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl)- amide 844 1-(6-Hydroxy-pyridazin-3-yl)-5-trifluoromethyl-1H- 389 pyrazole-4-carboxylic acid (1H-benzoimidazol-2-yl)- amide 845 1-(6-Hydroxy-pyridazin-3-yl)-5-trifluoromethyl-1H- 395 pyrazole-4-carboxylic acid [2-(2-fluoro-phenyl)-ethyl]- amide 846 1-(6-Hydroxy-pyridazin-3-yl)-5-trifluoromethyl-1H- 431 pyrazole-4-carboxylic acid 4-trifluoromethyl-benzylamide 847 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 408 carboxylic acid methyl-(2-pyridin-2-yl-ethyl)-amide 848 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 394 carboxylic acid methyl-pyridin-3-ylmethyl-amide 849 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 416 carboxylic acid quinolin-3-ylamide 850 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 533 carboxylic acid benzyl-(3-methanesulfonyl-phenyl)-amide 851 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 471 carboxylic acid ethyl-(3-methanesulfonyl-phenyl)-amide 852 [[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 529 carbonyl]-(3-methanesulfonyl-phenyl)-amino]-acetic acid ethyl ester 853 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 482 carboxylic acid cyanomethyl-(3-methanesulfonyl-phenyl)- amide 854 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 583 carboxylic acid (3-methanesulfonyl-phenyl)-naphthalen-2- ylmethyl-amide 855 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 534 carboxylic acid (3-methanesulfonyl-phenyl)-pyridin-3- ylmethyl-amide 856 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 534 carboxylic acid (3-methanesulfonyl-phenyl)-pyridin-2- ylmethyl-amide 857 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 567 carboxylic acid (4-chloro-benzyl)-(3-methanesulfonyl- phenyl)-amide 858 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 534 carboxylic acid (3-methanesulfonyl-phenyl)-pyridin-4- ylmethyl-amide 859 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 483 carboxylic acid allyl-(3-methanesulfonyl-phenyl)-amide 860 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 552 carboxylic acid (3,5-dimethyl-isoxazol-4-ylmethyl)-(3- 552 methanesulfonyl-phenyl)-amide 861 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 551 carboxylic acid benzyl-[2-(2,6-dichloro-phenyl)-ethyl]- amide 862 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 601 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]- naphthalen-2-ylmethyl-amide 863 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 552 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-pyridin-3- ylmethyl-amide 864 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 552 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-pyridin-2- 552 ylmethyl-amide 865 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 585 carboxylic acid (4-chloro-benzyl)-[2-(2,6-dichloro- phenyl)-ethyl]-amide 866 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 552 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-pyridin-4- ylmethyl-amide 867 1-Benzyl-3-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H- 394 pyrazol-4-yl]-urea 868 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 408 yl]-3-phenethyl-urea 869 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 426 yl]-3-[2-(4-fluoro-phenyl)-ethyl]-urea 870 Morpholine-4-carboxylic acid [1-(4-chloro-phenyl)-5- 374 trifluoromethyl-1H-pyrazol-4-yl]-amide 871 1-Butyl-3-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H- 360 pyrazol-4-yl]-urea 872 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 422 yl]-3-(2-m-tolyl-ethyl)-urea 873 1-[2-(4-Chloro-phenyl)-ethyl]-3-[1-(4-chloro-phenyl)-5- 442 trifluoromethyl-1H-pyrazol-4-yl]-urea 874 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 422 yl]-3-(3-phenyl-propyl)-urea 875 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 372 yl]-3-cyclopentyl-urea 876 1-Benzo[1,3]dioxol-5-ylmethyl-3-[1-(4-chloro-phenyl)-5- 438 trifluoromethyl-1H-pyrazol-4-yl]-urea 877 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 409 yl]-1-methyl-1-pyridin-3-ylmethyl-urea 878 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 423 yl]-1-methyl-1-(2-pyridin-2-yl-ethyl)-urea 879 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 414 carboxylic acid 3-trifluoromethyl-benzylamide 880 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 378 carboxylic acid [2-(2-fluoro-phenyl)-ethyl]-amide 881 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 372 carboxylic acid (1H-benzoimidazol-2-yl)-amide 882 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 333 carboxylic acid pyridin-4-ylamide 883 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 428 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-amide 884 1-(3-Chloro-phenyl)-3-[1-(4-chloro-phenyl)-5- 414 trifluoromethyl-1H-pyrazol-4-yl]-urea 885 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 448 yl]-3-(4-trifluoromethyl-phenyl)-urea 886 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 371 yl]-3-isoxazol-3-yl-urea 887 1-(2-tert-Butyl-phenyl)-3-[1-(4-chloro-phenyl)-5- 436 trifluoromethyl-1H-pyrazol-4-yl]-urea 888 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 380 yl]-3-phenyl-urea 889 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 445 yl]-3-(2-pyrrol-1-yl-phenyl)-urea 890 3-(2-Chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid 480 [1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- amide 891 1,3-Bis-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H- 548 pyrazol-4-yl]-urea 892 4-Acetyl-[1,4]diazepane-1-carboxylic acid [1-(4-chloro- 429 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 893 1-Allyl-3-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H- 344 pyrazol-4-yl]-urea 894 1-(2-Amino-benzyl)-3-[1-(4-chloro-phenyl)-5- 409 trifluoromethyl-1H-pyrazol-4-yl]-urea 895 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 445 yl]-3-(4-diethylamino-1-methyl-butyl)-urea 896 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 392 yl]-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea 897 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 465 yl]-3-[2-(ethyl-m-tolyl-amino)-ethyl]-urea 898 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 415 yl]-3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-urea 899 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 417 yl]-3-(2-morpholin-4-yl-ethyl)-urea 900 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 415 yl]-3-(2-piperidin-1-yl-ethyl)-urea 901 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 409 yl]-3-(2-pyridin-2-yl-ethyl)-urea 902 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 401 yl]-3-(2-pyrrolidin-1-yl-ethyl)-urea 903 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 420 yl]-3-(1H-indazol-6-yl)-urea 904 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 395 yl]-3-pyridin-3-ylmethyl-urea 905 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 395 yl]-3-pyridin-4-ylmethyl-urea 906 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 424 yl]-3-(2-hydroxy-2-phenyl-ethyl)-urea 907 1-[2-(4-Amino-phenyl)-ethyl]-3-[1-(4-chloro-phenyl)-5- 423 trifluoromethyl-1H-pyrazol-4-yl]-urea 908 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 446 yl]-3-(5-phenyl-2H-pyrazol-3-yl)-urea 909 (3-{3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol- 461 4-yl]-ureido}-propyl)-carbamic acid tert-butyl ester 910 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 412 yl]-3-(3-imidazol-1-yl-propyl)-urea 911 1-(1-Benzyl-pyrrolidin-3-yl)-3-[1-(4-chloro-phenyl)-5- 463 trifluoromethyl-1H-pyrazol-4-yl]-urea 912 4-Benzyl-piperazine-1-carboxylic acid [1-(4-chloro- 463 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 913 4-(2-Chloro-phenyl)-piperazine-1-carboxylic acid [1-(4- 483 chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 914 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 392 yl]-1,1-bis-(2-hydroxy-ethyl)-urea 915 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 403 yl]-3-(2-diethylamino-ethyl)-urea 916 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 417 yl]-3-(3-diethylamino-propyl)-urea 917 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 454 yl]-3-(2,3-dimethoxy-benzyl)-urea 918 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 454 yl]-3-(2,4-dimethoxy-benzyl)-urea 919 2,6-Dimethyl-morpholine-4-carboxylic acid [1-(4-chloro- 402 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 920 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 486 yl]-1,1-bis-pyridin-2-ylmethyl-urea 921 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 486 yl]-1,1-bis-pyridin-3-ylmethyl-urea 922 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 376 yl]-1-ethyl-1-(2-hydroxy-ethyl)-urea 923 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 423 yl]-1-ethyl-1-pyridin-4-ylmethyl-urea 924 v4-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid [1-(4- 417 chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 925 4-Methyl-[1,4]diazepane-1-carboxylic acid [1-(4-chloro- 401 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 926 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 415 yl]-1-methyl-1-(1-methyl-piperidin-4-yl)-urea 927 4-Methyl-piperazine-1-carboxylic acid [1-(4-chloro- 387 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 928 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 378 yl]-3-(2-methylsulfanyl-ethyl)-urea 929 4-Pyrimidin-2-yl-piperazine-1-carboxylic acid [1-(4- 451 chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 930 4-Benzo[1,3]dioxol-5-ylmethyl-piperazine-1-carboxylic 507 acid [1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- yl]-amide 931 3-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 448 yl]-1-(2-cyano-ethyl)-1-pyridin-3-ylmethyl-urea 932 3-Hydroxy-pyrrolidine-1-carboxylic acid [1-(4-chloro- 374 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 933 4-Pyrrolidin-1-yl-piperidine-1-carboxylic acid [1-(4- 441 chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-amide 934 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 388 yl]-3-(tetrahydro-furan-2-ylmethyl)-urea 935 Thiazolidine-3-carboxylic acid [1-(4-chloro-phenyl)-5- 376 trifluoromethyl-1H-pyrazol-4-yl]-amide 936 Thiomorpholine-4-carboxylic acid [1-(4-chloro-phenyl)-5- 390 trifluoromethyl-1H-pyrazol-4-yl]-amide 937 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 414 yl]-3-(2-thiophen-2-yl-ethyl)-urea 938 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4- 400 yl]-3-thiophen-2-ylmethyl-urea 939 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [1-(4- 430 trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-amide 940 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [1-(4- 430 trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-amide 941 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [1-(3- 430 trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-amide 942 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [1-(3- 430 trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-amide 943 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [1-(3- 414 trifluoromethyl-phenyl)-pyrrolidin-3-yl]-amide 944 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid [1-(3- 414 trifluoromethyl-phenyl)-pyrrolidin-3-yl]-amide 945 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 440 4-carboxylic acid 2,4-dimethoxy-benzylamide 946 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 424 4-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 947 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 384 4-carboxylic acid (3-fluoro-phenyl)-amide 948 [1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazol- 406 4-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone 949 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 396 4-carboxylic acid (3-methoxy-phenyl)-amide 950 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 406 4-carboxylic acid (2-isopropenyl-phenyl)-amide 951 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 381 4-carboxylic acid (pyridin-3-ylmethyl)-amide 952 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 462 4-carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-amide 953 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 451 4-carboxylic acid [2-(ethyl-m-tolyl-amino)-ethyl]-amide 954 [4-(2-Chloro-phenyl)-piperazin-1-yl]-[1-(6-chloro- 469 pyridin-2-yl)-5-trifluoromethyl-1H-pyrazol-4-yl]- methanone 955 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 449 4-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide 956 (4-Benzyl-piperazin-1-yl)-[1-(6-chloro-pyridin-2-yl)-5- 449 trifluoromethyl-1H-pyrazol-4-yl]-methanone 957 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 407 carboxylic acid 2,4-dimethoxy-benzylamide 958 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 391 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 959 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 351 carboxylic acid (3-fluoro-phenyl)-amide 960 (3,4-Dihydro-2H-quinolin-1-yl)-(1-pyrimidin-2-yl-5- 373 trifluoromethyl-1H-pyrazol-4-yl)-methanone 961 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 363 carboxylic acid (3-methoxy-phenyl)-amide 962 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 373 carboxylic acid (2-isopropenyl-phenyl)-amide 963 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 348 carboxylic acid (pyridin-3-ylmethyl)-amide 964 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 429 carboxylic acid [2-(2,6-dichloro-phenyl)-ethyl]-amide 965 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 418 carboxylic acid [2-(ethyl-m-tolyl-amino)-ethyl]-amide 966 [4-(2-Chloro-phenyl)-piperazin-1-yl]-(1-pyrimidin-2-yl-5- 436 trifluoromethyl-1H-pyrazol-4-yl)-methanone 967 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 416 carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide 968 (4-Benzyl-piperazin-1-yl)-(1-pyrimidin-2-yl-5- 416 trifluoromethyl-1H-pyrazol-4-yl)-methanone 969 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 489 pyrazole-4-carboxylic acid 2,4-dimethoxy-benzylamide 970 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 473 pyrazole-4-carboxylic acid (benzo[1,3]dioxol-5- ylmethyl)-amide 971 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 433 pyrazole-4-carboxylic acid (3-fluoro-phenyl)-amide 972 (3,4-Dihydro-2H-quinolin-1-yl)-[1-(4-trifluoromethoxy- 455 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-methanone 973 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 445 pyrazole-4-carboxylic acid (3-methoxy-phenyl)-amide 974 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 455 pyrazole-4-carboxylic acid (2-isopropenyl-phenyl)-amide 975 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 430 pyrazole-4-carboxylic acid (pyridin-3-ylmethyl)-amide 976 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 511 pyrazole-4-carboxylic acid [2-(2,6-dichloro-phenyl)- ethyl]-amide 977 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 500 pyrazole-4-carboxylic acid [2-(ethyl-m-tolyl-amino)- ethyl]-amide 978 [4-(2-Chloro-phenyl)-piperazin-1-yl]-[1-(4- 518 trifluoromethoxy-phenyl)-5-trifluoromethyl-1H-pyrazol-4- yl]-methanone 979 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 498 pyrazole-4-carboxylic acid (1-benzyl-pyrrolidin-3-yl)- amide 980 (4-Benzyl-piperazin-1-yl)-[1-(4-trifluoromethoxy-phenyl)- 498 5-trifluoromethyl-1H-pyrazol-4-yl]-methanone 981 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 406 carboxylic acid 2,4-dimethoxy-benzylamide 982 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 390 carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 983 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 350 carboxylic acid (3-fluoro-phenyl)-amide 984 (3,4-Dihydro-2H-quinolin-1-yl)-(1-pyridin-2-yl-5- 372 trifluoromethyl-1H-pyrazol-4-yl)-methanone 985 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 362 carboxylic acid (3-methoxy-phenyl)-amide 986 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 372 carboxylic acid (2-isopropenyl-phenyl)-amide 987 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 347 carboxylic acid (pyridin-3-ylmethyl)-amide 988 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 417 carboxylic acid [2-(ethyl-m-tolyl-amino)-ethyl]-amide 989 [4-(2-Chloro-phenyl)-piperazin-1-yl]-(1-pyridin-2-yl-5- 435 trifluoromethyl-1H-pyrazol-4-yl)-methanone 990 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 415 carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide 991 (4-Benzyl-piperazin-1-yl)-(1-pyridin-2-yl-5- 415 trifluoromethyl-1H-pyrazol-4-yl)-methanone 992 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 450 4-carboxylic acid (2-trifluoromethoxy-phenyl)-amide 993 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 422 4-carboxylic acid (4-tert-butyl-phenyl)-amide 994 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 472 4-carboxylic acid bis-pyridin-2-ylmethyl-amide 995 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 428 4-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 996 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 412 4-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide 997 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 398 4-carboxylic acid (4-fluoro-phenyl)-methyl-amide 998 4-{[1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H- 438 pyrazole-4-carbonyl]-amino}-benzoic acid ethyl ester 999 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 431 4-carboxylic acid (2-pyrrol-1-yl-phenyl)-amide 1000 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 401 4-carboxylic acid (5-chloro-pyridin-2-yl)-amide 1001 1-(6-Chloro-pyridin-2-yl)-5-trifluoromethyl-1H-pyrazole- 417 4-carboxylic acid isoquinolin-1-ylamide 1002 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 417 carboxylic acid (2-trifluoromethoxy-phenyl)-amide 1003 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 389 carboxylic acid (4-tert-butyl-phenyl)-amide 1004 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 439 carboxylic acid bis-pyridin-2-ylmethyl-amide 1005 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 395 carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 1006 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 379 carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide 1007 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 365 carboxylic acid (4-fluoro-phenyl)-methyl-amide 1008 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 411 carboxylic acid (3-methanesulfonyl-phenyl)-amide 1009 4-[(1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 405 carbonyl)-amino]-benzoic acid ethyl ester 1010 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 398 carboxylic acid (2-pyrrol-1-yl-phenyl)-amide 1011 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 368 carboxylic acid (5-chloro-pyridin-2-yl)-amide 1012 1-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 384 carboxylic acid isoquinolin-1-ylamide 1013 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 499 pyrazole-4-carboxylic acid (2-trifluoromethoxy-phenyl)- amide 1014 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 471 pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide 1015 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 521 pyrazole-4-carboxylic acid bis-pyridin-2-ylmethyl-amide 1016 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 477 pyrazole-4-carboxylic acid [2-(4-chloro-phenyl)-ethyl]- amide 1017 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 461 pyrazole-4-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]- amide 1018 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 447 pyrazole-4-carboxylic acid (4-fluoro-phenyl)-methyl- amide 1019 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 493 pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl)- amide 1020 4-{[1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 487 pyrazole-4-carbonyl]-amino}-benzoic acid ethyl ester 1021 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 480 pyrazole-4-carboxylic acid (2-pyrrol-1-yl-phenyl)-amide 1022 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 450 pyrazole-4-carboxylic acid (5-chloro-pyridin-2-yl)-amide 1023 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 466 pyrazole-4-carboxylic acid isoquinolin-1-ylamide 1024 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 416 carboxylic acid (2-trifluoromethoxy-phenyl)-amide 1025 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 388 carboxylic acid (4-tert-butyl-phenyl)-amide 1026 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 438 carboxylic acid bis-pyridin-2-ylmethyl-amide 1027 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 394 carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide 1028 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 378 carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide 1029 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 364 carboxylic acid (4-fluoro-phenyl)-methyl-amide 1030 4-[(1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 404 carbonyl)-amino]-benzoic acid ethyl ester 1031 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 397 carboxylic acid (2-pyrrol-1-yl-phenyl)-amide 1032 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 367 carboxylic acid (5-chloro-pyridin-2-yl)-amide 1033 1-Pyridin-2-yl-5-trifluoromethyl-1H-pyrazole-4- 383 carboxylic acid isoquinolin-1-ylamide 1034 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 450 carboxylic acid [2-(ethyl-m-tolyl-amino)-ethyl]-amide 1035 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 448 carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide 1036 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 448 carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide 1037 1-(1-Benzyl-pyrrolidin-3-yl)-3-[1-(4-chloro-phenyl)-5- 463 trifluoromethyl-1H-pyrazol-4-yl]-urea 1038 1-(1-Benzyl-pyrrolidin-3-yl)-3-[1-(4-chloro-phenyl)-5- 463 trifluoromethyl-1H-pyrazol-4-yl]-urea 1039 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 462 carboxylic acid (1-benzyl-piperidin-4-yl)-amide 1040 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 372 carboxylic acid piperidin-4-ylamide 1041 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 451 carboxylic acid (1-sulfamoyl-piperidin-4-yl)-amide 1042 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 479 carboxylic acid (1-dimethylsulfamoyl-piperidin-4-yl)- amide 1044 4-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 444 4-carbonyl]-amino}-piperidine-1-carboxylic acid ethyl ester 1045 {1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 472 4-carbonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester 1046 (4-Amino-piperidin-1-yl)-[1-(4-chloro-phenyl)-5- 372 trifluoromethyl-1H-pyrazol-4-yl]-methanone 1049 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 399 carboxylic acid (3-chloro-phenyl)-amide 1050 3-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 437 4-carbonyl]-amino}-benzoic acid ethyl ester 1052 3-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 409 4-carbonyl]-amino}-benzoic acid 1053 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 460 carboxylic acid [3-(3,5-dimethyl-isoxazol-4-yl)-phenyl]- amide 1054 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 444 carboxylic acid (3-sulfamoyl-phenyl)-amide 1055 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 472 carboxylic acid (3-dimethylsulfamoyl-phenyl)-amide 1056 (4-Benzylamino-piperidin-1-yl)-[1-(4-chloro-phenyl)-5- 462 trifluoromethyl-1H-pyrazol-4-yl]-methanone 1057 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 480 [4-(4-fluoro-benzylamino)-piperidin-1-yl]-methanone 1058 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 492 [4-(4-methoxy-benzylamino)-piperidin-1-yl]-methanone 1059 [4-(4-Chloro-benzylamino)-piperidin-1-yl]-[1-(4-chloro- 496 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-methanone 1060 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 480 carboxylic acid [1-(4-fluoro-benzyl)-piperidin-4-yl]-amide 1061 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 496 carboxylic acid [1-(3-chloro-benzyl)-piperidin-4-yl]- amide 1062 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 480 carboxylic acid [1-(2-fluoro-benzyl)-piperidin-4-yl]-amide 1063 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 546 carboxylic acid [1-(4-trifluoromethoxy-benzyl)-piperidin- 4-yl]-amide 1064 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 554 carbonyl]-piperidine-2-carboxylic acid (3- methanesulfonyl-phenyl)-amide 1065 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 373 (4-hydroxy-piperidin-1-yl)-methanone 1066 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 491 [2-(5-fluoro-1H-benzoimidazol-2-yl)-piperidin-1-yl]- methanone 1067 [2-(1H-Benzoimidazol-2-yl)-piperidin-1-yl]-[1-(4-chloro- 473 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-methanone 1068 1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 427 carboxylic acid (3-methanesulfonyl-phenyl)-amide 1069 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 445 carboxylic acid (3-methanesulfonyl-phenyl)-amide 1070 1-(3-Fluoro-phenyl)-5-tifluoromethyl-1H-pyrazole-4- 377 carboxylic acid phenethyl-amide 1071 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 395 carboxylic acid phenethyl-amide 1072 1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 377 carboxylic acid benzyl-methyl-amide 1073 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 395 carboxylic acid benzyl-methyl-amide 1074 1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 431 carboxylic acid 3-trifluoromethyl-benzylamide 1075 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 449 carboxylic acid 3-trifluoromethyl-benzylamide 1076 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 504 carbonyl]-piperidine-2-carboxylic acid phenethyl-amide 1077 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 504 carbonyl]-piperidine-2-carboxylic acid benzyl-methyl- amide 1078 1-[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 558 carbonyl]-piperidine-2-carboxylic acid 3-trifluoromethyl- benzylamide 1079 1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 446 carboxylic acid (1-benzyl-pyrrolidin-3-yl)-methyl-amide 1080 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 464 carboxylic acid (1-benzyl-pyrrolidin-3-yl)-methyl-amide 1081 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 512 pyrazole-4-carboxylic acid (1-benzyl-pyrrolidin-3-yl)- methyl-amide 1082 1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 450 carboxylic acid (5-diisopropylamino-pyrimidin-2-yl)- amide 1083 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 468 carboxylic acid (5-diisopropylamino-pyrimidin-2-yl)- amide 1084 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 516 pyrazole-4-carboxylic acid (5-diisopropylamino- pyrimidin-2-yl)-amide 1085 1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 428 carboxylic acid (3-sulfamoyl-phenyl)-amide 1086 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 446 carboxylic acid (3-sulfamoyl-phenyl)-amide 1087 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 494 pyrazole-4-carboxylic acid (3-sulfamoyl-phenyl)-amide 1088 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 443 carboxylic acid (2-chloro-pyrimidin-5-yl)-amide 1089 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 448 carboxylic acid (3-thiazol-2-yl-phenyl)-amide 1090 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 461 carboxylic acid [3-(3-methyl-5-oxo-4,5-dihydro-pyrazol- 1-yl)-phenyl]-amide 1091 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 482 carboxylic acid (3-benzooxazol-2-yl-phenyl)-amide 1092 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 408 carboxylic acid (3-carbamoyl-phenyl)-amide 1093 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 408 carboxylic acid (3-dimethylamino-phenyl)-amide 1094 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 473 carboxylic acid [3-(2-hydroxy-ethanesulfonyl)-phenyl]- amide 1095 4-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 472 4-carbonyl]-amino}-piperidine-1-carboxylic acid tert- butyl ester 1096 1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 429 carboxylic acid (2-methyl-5-phenyl-2H-pyrazol-3-yl)- amide 1097 (4-Benzyl-piperazin-1-yl)-[1-(3-fluoro-phenyl)-5- 432 trifluoromethyl-1H-pyrazol-4-yl]-methanone 1098 1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 350 carboxylic acid pyridin-4-ylamide 1099 Biphenyl-3-carboxylic acid (2-methyl-5-phenyl-2H- 353 pyrazol-3-yl)-amide 1100 Biphenyl-4-carboxylic acid (2-methyl-5-phenyl-2H- 353 pyrazol-3-yl)-amide 1101 4′-Chloro-biphenyl-3-carboxylic acid (2-methyl-5-phenyl- 387 2H-pyrazol-3-yl)-amide 1102 3-{[1-(3-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 456 carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester 1103 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 447 carboxylic acid (2-methyl-5-phenyl-2H-pyrazol-3-yl)- amide 1104 (4-Benzyl-piperazin-1-yl)-[1-(3,4-difluoro-phenyl)-5- 450 trifluoromethyl-1H-pyrazol-4-yl]-methanone 1105 1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 368 carboxylic acid pyridin-4-ylamide 1106 3-{[1-(3,4-Difluoro-phenyl)-5-trifluoromethyl-1H- 474 pyrazole-4-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester 1107 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 514 carboxylic acid [3-(morpholine-4-sulfonyl)-phenyl]-amide 1108 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 495 pyrazole-4-carboxylic acid (2-methyl-5-phenyl-2H- pyrazol-3-yl)-amide 1109 1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 416 pyrazole-4-carboxylic acid pyridin-4-ylamide 1110 3-{[1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethyl-1H- 522 pyrazole-4-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester 1111 Methanesulfonic acid 1-[1-(4-chloro-phenyl)-5- 451 trifluoromethyl-1H-pyrazole-4-carbonyl]-piperidin-4-yl ester 1112 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid (3-methylsulfamoyl-phenyl)-amide 1113 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 442 carboxylic acid (3-pyridin-2-yl-phenyl)-amide 1114 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 442 carboxylic acid (3-pyridin-3-yl-phenyl)-amide 1115 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 442 carboxylic acid (3-pyridin-4-yl-phenyl)-amide 1116 1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 428 carboxylic acid (3-sulfamoyl-phenyl)-amide 1117 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 497 carboxylic acid (3-trifluoromethanesulfonyl-phenyl)- amide 1118 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid (3-methanesulfonylamino-phenyl)-amide 1119 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 433 carboxylic acid [3-(2H-tetrazol-5-yl)-phenyl]-amide 1120 [(3-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-phenyl)-imino-methyl]-carbamic acid tert-butyl ester 1121 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- carboxylic acid (3-carbamimidoyl-phenyl)-amide 1122 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 380 carboxylic acid (3-amino-phenyl)-amide 1123 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- carboxylic acid (3-ureido-phenyl)-amide 1127 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 444 carboxylic acid (4-sulfamoyl-phenyl)-amide 1130 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 422 carboxylic acid (3-acetylamino-phenyl)-amide 1131 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 484 carboxylic acid (3-cyclopropylsulfamoyl-phenyl)-amide 1132 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 449 (4-pyridin-2-ylmethyl-piperazin-1-yl)-methanone 1133 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 449 (4-pyridin-3-ylmethyl-piperazin-1-yl)-methanone 1134 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 449 (4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone 1135 [1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]- 469 [4-(1-methyl-piperidin-3-ylmethyl)-piperazin-1-yl]- methanone 1136 2-Phenyl-2H-pyrazole-3-carboxylic acid pyridin-4- 264 ylamide 1137 (4-Benzyl-piperazin-1-yl)-(2-phenyl-2H-pyrazol-3-yl)- 346 methanone 1138 2-Phenyl-2H-pyrazole-3-carboxylic acid (3- 341 methanesulfonyl-phenyl)-amide 1139 2-Phenyl-2H-pyrazole-3-carboxylic acid (1H- 303 benzoimidazol-2-yl)-amide 1140 2-Phenyl-2H-pyrazole-3-carboxylic acid 3- 345 trifluoromethyl-benzylamide 1141 2-Phenyl-2H-pyrazole-3-carboxylic acid (2-methyl-5- 343 phenyl-2H-pyrazol-3-yl)-amide 1142 2-Phenyl-2H-pyrazole-3-carboxylic acid (3-sulfamoyl- 342 phenyl)-amide 1143 2-Phenyl-2H-pyrazole-3-carboxylic acid (1-benzyl- 360 piperidin-4-yl)-amide 1144 2-Phenyl-2H-pyrazole-3-carboxylic acid (1-benzyl- 346 pyrrolidin-3-yl)-amide 1145 2-Phenyl-2H-pyrazole-3-carboxylic acid (1-benzyl- 346 pyrrolidin-3-yl)-amide 1146 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 411 carboxylic acid (3-methylsulfanyl-phenyl)-amide 1147 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 427 carboxylic acid (3-methanesulfinyl-phenyl)-amide 1148 3-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole- 445 4-carbonyl]-amino}-benzenesulfonic acid 1151 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 577 carboxylic acid {3-[(methanesulfonylimino-phenoxy- methyl)-amino]-phenyl}-amide 1152 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 500 carboxylic acid {3-[(amino-methanesulfonylimino- methyl)-amino]-phenyl}-amide 1153 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 514 carboxylic acid {3-[(methanesulfonylimino-methylamino- methyl)-amino]-phenyl}-amide 1154 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 540 carboxylic acid {3-[(cyclopropylamino- methanesulfonylimino-methyl)-amino]-phenyl}-amide 1155 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 528 carboxylic acid {3-[(dimethylamino- methanesulfonylimino-methyl)-amino]-phenyl}-amide 1156 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 556 carboxylic acid (3-{[(isopropyl-methyl-amino)- methanesulfonylimino-methyl]-amino}-phenyl)-amide 1157 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 594 carboxylic acid [3-(2,4-dimethoxy-benzylsulfamoyl)- phenyl]-amide 1158 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 555 carboxylic acid [3-(2-piperidin-1-yl-ethylsulfamoyl)- phenyl]-amide 1159 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 557 carboxylic acid [3-(3-diethylamino-propylsulfamoyl)- phenyl]-amide 1160 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 594 carboxylic acid [3-(2,3-dimethoxy-benzylsulfamoyl)- phenyl]-amide 1161 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 569 carboxylic acid {3-[3-(2-oxo-pyrrolidin-1-yl)- propylsulfamoyl]-phenyl}-amide 1162 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 605 carboxylic acid {3-[2-(ethyl-m-tolyl-amino)- ethylsulfamoyl]-phenyl}-amide 1163 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 514 carboxylic acid [3-(3-hydroxy-pyrrolidine-1-sulfonyl)- phenyl]-amide 1164 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 500 carboxylic acid (3-butylsulfamoyl-phenyl)-amide 1165 [3-(3-{[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H- 601 pyrazole-4-carbonyl]-amino}-benzenesulfonylamino)- propyl]-carbamic acid tert-butyl ester 1166 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 514 carboxylic acid [3-(3-hydroxy-pyrrolidine-1-sulfonyl)- phenyl]-amide 1167 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 502 carboxylic acid [3-(2-hydroxy-propylsulfamoyl)-phenyl]- amide 1168 (4-Benzyl-piperazin-1-yl)-[1-(4-chloro-phenyl)-5- 448 trifluoromethyl-1H-pyrazol-4-yl]-methanone 1169 (4-Benzyl-4-hydroxy-piperidin-1-yl)-[1-(4-chloro- 463 phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-methanone 1170 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 555 carboxylic acid {3-[(1-ethyl-pyrrolidin-2-ylmethyl)- sulfamoyl]-phenyl}-amide 1171 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 543 carboxylic acid [3-(2-diethylamino-ethylsulfamoyl)- phenyl]-amide 1172 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 563 carboxylic acid {3-[2-(4-amino-phenyl)-ethylsulfamoyl]- phenyl}-amide 1173 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 541 carboxylic acid [3-(2-pyrrolidin-1-yl-ethylsulfamoyl)- phenyl]-amide 1174 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 535 carboxylic acid {3-[(pyridin-3-ylmethyl)-sulfamoyl]- phenyl}-amide 1175 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 515 carboxylic acid [3-(2-dimethylamino-ethylsulfamoyl)- phenyl]-amide 1176 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 530 carboxylic acid [3-(thiomorpholine-4-sulfonyl)-phenyl]- amide 1177 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 541 carboxylic acid [3-(4-methyl-[1,4]diazepane-1-sulfonyl)- phenyl]-amide 1178 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 527 carboxylic acid [3-(4-methyl-piperazine-1-sulfonyl)- phenyl]-amide 1179 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 582 carboxylic acid {3-[2-(3-chloro-phenyl)-ethylsulfamoyl]-phenyl}- amide 1180 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 563 carboxylic acid {3-[methyl-(2-pyridin-2-yl-ethyl)-sulfamoyl]- phenyl}-amide 1181 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 472 carboxylic acid (3-ethylsulfamoyl-phenyl)-amide 1182 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 502 carboxylic acid {3-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-phenyl}- amide 1183 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 500 carboxylic acid (3-diethylsulfamoyl-phenyl)-amide 1184 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 500 carboxylic acid (6-methanesulfonyl-benzothiazol-2-yl)-amide 1185 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid (2-methyl-3-sulfamoyl-phenyl)-amide 1186 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 458 carboxylic acid (2-sulfamoylmethyl-phenyl)-amide 1187 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 478 carboxylic acid (2-chloro-5-sulfamoyl-phenyl)-amide 1188 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4- 465 carboxylic acid (4-methyl-5-sulfamoyl-thiazol-2-yl)-amide

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to included within the spirit and purview of this application and are considered within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. 

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl, (C₁-C₆)heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl; R² is a member selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl; Y is a member selected from:

wherein X is a member selected from O, S and NR⁸ wherein R⁸ is a member selected from the group of hydrogen, cyano, nitro, alkyl, acyl, aryl and SO₂R⁹ wherein R⁹ is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl; R⁴ and R⁵ are each members independently selected from hydrogen, (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₃-C₈)heterocycloalkyl with the proviso that if R⁴ is hydrogen, R⁵ is not hydrogen; and R⁴ and R⁵ taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring; R⁶ is a member selected from hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₁-C₆)heteroalkyl; and R⁷ is a member selected from (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkenyl, (C₁-C₆)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino, alkoxy, (C₃-C₈)heterocycloalkyl and amino(C₁-C₅)alkyl, and and R⁶ and R⁷ together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.
 2. The compound of claim 1 having the formula:


3. The compound of claim 2 wherein Y has a formula which is a member selected from:


4. The compound of claim 3 wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl and (C₁-C₅)heteroalkyl; and X is O.
 5. The compound of claim 4 wherein R² is a member selected from aryl and heteroaryl.
 6. The compound of claim 5 wherein R³ is hydrogen.
 7. The compound according to claim 6 wherein R¹ is a member selected from hydrogen, (C₁-C₄)alkyl, and (C₁-C₄)haloalkyl.
 8. The compound according to claim 3 wherein R⁴ is a member selected from heteroaryl and heterocycloalkyl; and R⁴ and R⁵, together with the nitrogen to which they are bonded are optionally joined to form a 4- to 8-membered heterocycloalkyl ring system.
 9. The compound according to claim 8, wherein R⁴ and R⁵ taken together with the nitrogen to which they are attached form a member selected from:


10. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl, (C₁-C₆)heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl; R² is a member selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl; Y is a member selected from:

wherein X is a member selected from O, S and NR⁸ wherein R⁸ is a member selected from hydrogen, cyano, nitro, alkyl, acyl, aryl and SO₂R⁹ wherein R⁹ is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl; R⁴ has a formula which is a member selected from:

wherein n is an integer from 0 to 4; k is an integer from 1 to 3; R^(2a) and R^(2b) are members independently selected from hydrogen and (C₁-C₄)alkyl, and R^(2a) and R^(2b) taken together with the carbon atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocycloalkyl ring; M is a member selected from NR¹⁰, O and S wherein R¹⁰ is a member selected from hydrogen, (C₁-C₆) alkyl, (C₁-C₈) heteroalkyl aryl, heteroaryl and (C₃-C₈) cycloalkyl; A, B, D, E and G are independently members selected from N, N-oxide and CR¹¹ with the proviso that at most three of A, B, D, E and G is N; and at most one of A, B, D, E and G is N-oxide wherein R¹¹ is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)heteroalkyl, aryl, heteroaryl, (C₃-C₈)heterocycloalkyl, alkoxy, acyl, —C(NR¹²)R¹³, —SO₂R¹⁵, —SO₂NR¹³R¹⁴, —NR¹²SOR¹⁵, —NR¹²SO₂NR¹³R¹⁴, —NR¹²C(N—CN)NR¹³R¹⁴, —NR¹²C(N—SO₂R¹⁵)NR¹³R¹⁴, —NR¹²C(N—COR¹⁵)NR¹³R¹⁴, —CONR¹³R¹⁴, —NR¹²(C═CH—NO₂)NR¹³R¹⁴, —NR¹²CONR¹³R¹⁴, —NR¹²CO—OR¹⁵, —OCONR¹³R¹⁴ and R¹¹ and R^(2a) taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl group with the proviso that A is CR¹¹ wherein R^(11a) is a member selected from (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₈)heterocycloalkyl, aryl and heteroaryl; R¹², R¹³ and R¹⁴ are members independently selected from hydrogen, (C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl, (C₃-C₈)heterocycloalkyl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino(C₁-C₄)alkyl and when R¹³ and R¹⁴ are attached to the same nitrogen atom, they are optionally combined to form a 5-, 6- or 7-membered ring; R¹⁵ is a member selected from (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl and (C₃-C₈)heterocycloalkyl; R⁵ is a member selected from hydrogen and (C₁-C₄)alkyl; and R⁵ and R¹¹ taken together with the atoms to which that are attached optionally form a 4- to 8-membered heterocycloalkyl ring with the proviso that A is CR¹¹ R⁶ is a member selected from hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₁-C₆)heteroalkyl; and R⁷ is a member selected from (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkenyl, (C₁-C₆)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino, alkoxy, (C₃-C₈)heterocycloalkyl and amino(C₁-C₅)alkyl, and R⁶ and R⁷ taken together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.
 11. The compound of claim 10 wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl and (C₁-C₅)heteroalkyl; and X is O.
 12. The compound of claim 11 wherein R² is a member selected from aryl and heteroaryl.
 13. The compound of claim 11 wherein one only of A, B, C, D or E is an N or N-oxide.
 14. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl, (C₁-C₆)heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl; R² is a member selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl; Y is a member selected from:

R⁴ has a formula which is a member selected from:

wherein W is a member selected from S, SO and SO₂; n is an integer from 0 to 4; R^(2a) and R^(2b) are members independently selected from hydrogen and (C₁-C₄)alkyl, and R^(2a) and R^(2b) taken together with the carbon atom to which they are attached optionally form a 3- to 8-membered carbocyclic or heterocycloalkyl ring; R¹⁵ is a member selected from (C₁-C₄)alkyl, (C₁-C₆)alkenyl, (C₃-C₇)cycloalkyl, aryl, heteroaryl, (C₁-C₈)heteroalkyl, NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷ are members independently selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, (C₃-C₈)heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino(C₁-C₄)alkyl, with the proviso that when R¹⁵ is amino W is SO₂; T¹, T², T³ and T⁴ are each members independently selected from hydrogen, halo, amino, cyano, nitro, (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₄)haloalkyl, alkoxy, fluoro(C₁-C₄)alkoxy, (C₁-C₇)cycloalkyl, (C₁-C₇)heteroalkyl, aryl and heteroaryl, and T¹ and T² taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring; T² and T³ taken together with the carbon atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring; T³ and R¹⁵ taken together with the atoms to which they are attached optionally form a 4- to 8-membered carbocyclic or heterocycloalkyl ring; and T⁴ and R¹⁵ taken together with the atoms to which they are attached optionally form a 4-to 8-membered carbocyclic or heterocycloalkyl ring; and R⁵ is a member selected from hydrogen and (C₁-C₄)alkyl; R⁵ and T¹ taken together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring, and R⁵ and T⁴ taken together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.
 15. The compound of claim 14 wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl and (C₁-C₅)heteroalkyl; and X is O.
 16. The compound of claim 14 wherein R² is a member selected from aryl and heteroaryl.
 17. The compound of claim 15 wherein W is SO₂; and R¹¹ is selected from substituted or unsubstituted (C₁-C₄)alkyl and NR¹⁶R¹⁷; and n is
 0. 18. A method of decreasing ion flow through voltage-dependent sodium channels in a cell, said method comprising contacting said cell with a sodium channel-inhibiting amount of a compound comprising a pyrazolyl moiety.
 19. The method according to claim 18, wherein said cell is in a human.
 20. A method of decreasing ion flow through voltage-dependent sodium channels in a cell, said method comprising contacting said cell with a sodium channel-inhibiting amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl, (C₁-C₆)heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl; R² is a member selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl; Y is a member selected from:

wherein X is a member selected from O, S and NR⁸ wherein R⁸ is a member selected from the group of hydrogen, cyano, nitro, alkyl, acyl, aryl and SO₂R⁹ wherein R⁹ is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl; R⁴ and R⁵ are each members independently selected from hydrogen, (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₃-C₈)heterocycloalkyl with the proviso that if R⁴ is hydrogen, R⁵ is not hydrogen; and R⁴ and R⁵ taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring; R⁶ is a member selected from hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₁-C₆)heteroalkyl; and R⁷ is a member selected from (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkenyl, (C₁-C₆)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino, alkoxy, (C₃-C₈)heterocycloalkyl and amino(C₁-C₅)alkyl, and and R⁶ and R⁷ together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.
 21. A method of treating a central or peripheral nervous system disorder or condition through inhibition of a voltage-dependent sodium channel, said method comprising administering to a subject in need of such treatment, an effective amount of a compound comprising a pyrazolyl moiety.
 22. The method according to claim 21, said compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl, (C₁-C₆)heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl; R² is a member selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl; Y is a member selected from:

wherein X is a member selected from O, S and NR⁸ wherein R⁸ is a member selected from the group of hydrogen, cyano, nitro, alkyl, acyl, aryl and SO₂R⁹ wherein R⁹ is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl; R⁴ and R⁵ are each members independently selected from hydrogen, (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₃-C₈)heterocycloalkyl with the proviso that if R⁴ is hydrogen, R⁵ is not hydrogen; and R⁴ and R⁵ taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring; R⁶ is a member selected from hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₁-C₆)heteroalkyl; and R⁷ is a member selected from (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkenyl, (C₁-C₆)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino, alkoxy, (C₃-C₈)heterocycloalkyl and amino(C₁-C₅)alkyl, and and R⁶ and R⁷ together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring.
 23. The method according to claim 20, wherein said disorder is pain selected from inflammatory pain, neuropathic pain and combinations thereof.
 24. A composition comprising a pharmaceutically acceptable excipient and a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R³ are each members independently selected from hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₄)haloalkyl, (C₁-C₆)heteroalkyl, amino, halo, cyano, nitro, hydroxy, aryl and heteroaryl; R² is a member selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₇)cycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl; Y is a member selected from:

wherein X is a member selected from O, S and NR⁸ wherein R⁸ is a member selected from the group of hydrogen, cyano, nitro, alkyl, acyl, aryl and SO₂R⁹ wherein R⁹ is a member selected from alkyl, aryl, heteroaryl and heterocycloalkyl; R⁴ and R⁵ are each members independently selected from hydrogen, (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₈)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₃-C₈)heterocycloalkyl with the proviso that if R⁴ is hydrogen, R⁵ is not hydrogen; and R⁴ and R⁵ taken together with the nitrogen atom to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring; R⁶ is a member selected from hydrogen, (C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl and (C₁-C₆)heteroalkyl; and R⁷ is a member selected from (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₇)alkenyl, (C₁-C₆)heteroalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)alkyl, amino, alkoxy, (C₃-C₈)heterocycloalkyl and amino(C₁-C₅)alkyl, and and R⁶ and R⁷ together with the atoms to which they are attached optionally form a 4- to 8-membered heterocycloalkyl ring. 